CN104906063A - Release way and preparation method of novel compound sleeping controlled release preparation - Google Patents
Release way and preparation method of novel compound sleeping controlled release preparation Download PDFInfo
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Abstract
The invention discloses a novel compound sleeping pill, including a quick release drug release layer and a sustained and controlled release drug release layer. The two layers respectively contain a same sleeping pill or different sleeping pills, and the double layer tablet shows 15 min of rapid dissolution and up to 4 hours of slow dissolution after 2 h. By taking the double layer tablet, the effects of fast sleeping and early awakening prevention of a patient can be achieved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to the preparation method of the delivery mode of the sleeping controlled release preparation of a kind of novel compound, preparation composition and said preparation.
Background technology
25916 patients that at primary care go to a doctor regional to 15,14 countries according to World Health Organization (WHO) investigate, and the people finding that there is 27% has sleeping problems.It is reported, the insomnia incidence rate of the U.S. is up to 32% to 50%, and Britain is 10% to 14%, and Japan is 20%, and France is 30%, and China is also more than 30%.The symptom of insomnia generally shows as that difficulty falling asleep, sleep table are shallow, Yi Xing, early awakening etc.
Early awakening is the one of the obstacle of sleep, shows as and wakes up in advance compared with the recovery time of self sleep rule and can not fall asleep again.General 2 ~ 3 hs more Zao than normal condition or longer time.The sleeping pill of current rapid release often discharges comparatively fast, cannot treat early awakening symptom.If but take there is slow releasing function sleeping medicine to extend the length of one's sleep, often can cause again the drug residue effect in morning next day, impact normally works, lives.In order to provide a kind of high-quality, effective therapeutic scheme to insomniac, develop a kind of novel compound sleeping pill.It has twice release: rapid release of active composition for the first time, enables patient fall asleep fast; Second time slow releasing after taking several hours, thus prevent patient's early awakening.
Sedative hypnotics one has three generations, and first generation sedative hypnotics includes barbiturates, chloral hydrate, mixture tribromide and atarax etc.Barbiturates is the sedative hypnotics occurred the earliest, phenobarbital price comparison is low, be mainly used in calmness and antiepileptic action clinically, even if because its short-term is taken, easily form dependence after drug withdrawal, benzodiazepine is compared in untoward reaction and other classes are comparatively large, and phenobarbital is Liver enzyme inducer, share with other drug and can affect its metabolism, in Clinical practice mostly replace by benzodiazepine medicine.In first generation sedative hypnotics, chloral hydrate causes does not have too large side effect, and is widely used in clinical trial and quick hypnosis, and atarax is applicable to the patient of autonomic nervous dysfunction.In rising, the phenobarbital of barbiturates can carry out substituting and step-down therapy to his hypnotic, multiplexly treats in diseases such as child's sleep walking, sleep terrors and nightmares, can also be used for the central excitation untoward reaction of the medicines such as antagonism ephedrine, amfetamine, aminophylline.
Second filial generation sedative hypnotics mainly refers to benzodiazepine sedative hypnotic.Benzodiazepine sedative hypnotic is that the most frequently used clinically one is calm, hypnosis and antianxiety drugs.What such medicine mid-early stage developed has methaqualone, first third ammonia vinegar, chlorine nitrogen, diazepam, sulpiride, triazolam, midazolam, flurazepam, nitrazepam, estazolam, alprazolam, lorazepam etc.Such medicine can induce patient falls asleep rapidly, reduces night and to awaken number of times, extends and turns round and look at the dormancy time and improve sleep quality.Therapeutic index level is high, and low to Viscus toxicity, can use safely.So far, such medicine is still the conventional medicine of Cure for insomnia.
Benzodiazepine medicine respectively has feature.As triazolam: absorbing fast, rapid-action, without accumulation, without aftereffect, is comparatively ideal hypnotic drug; But shortcoming is that the half-life is short, after medication, easily produce insomnia in early morning and daytime anxiety., seldom there is insomnia in early morning and daytime anxiety in flurazepam: the half-life is longer, but has activity due to its main metabolites, and the active metabolite half-life reaches 47 ~ 100 h, therefore easily accumulate.
Third generation sedative hypnotic drug mainly comprises zolpidem, Zaleplon, zopiclone.In the later stage eighties 20th century, be developed zolpidem class medicine.Such medicine can show shortening time for falling asleep, reduces night and to awaken number of times, improving water flood quality, also seldom produces " being still drank after a night " phenomenon simultaneously, does not affect the life and work of next day.And such medicine is without additive, use safer, be subject to liking of broad masses.This kind of safer hypnotic comprises zopiclone (also thinking dream), Zaleplon (En Nuoxin), zolpidem (Stilnox) etc.
At present, the research of domestic and international sustained-release preparation is comparatively ripe, the advantage of sustained-release preparation is maintain drug disposition valid density in a long time, reduce adverse drug reaction, improve the compliance of patient medication, but sustained-release preparation comparatively ordinary preparation also has weak point, as slow in release, onset is slow.In recent years, start both at home and abroad to develop a kind of two-phase medicine-releasing system (Biphasic drug delivery system) with two different release phases, also two delivery formulations is claimed, to realizing the effect of rapid release and slow release, biphasic controlled release, rapid release and time controlled released simultaneously.
The feature of two-phase medicine-releasing system: 1, the Accumulation dissolution of regulating drug, plays long-acting; 2, reduce side effect, alleviate GI irritation; 3, bioavailability is improved; 4, Multiple components synergism.As 2014, China Medicine University Li Juan etc. invented the Orally taken pulsed controlled-release administrating system of a kind of Zolpidemtar Trate (CN 103976972 A).This system and compositions thereof comprise: A, submicron solid dispersion medicine; B, solubilizing systems pastille inner layer piece; C, pulse controlled release portion (being made up of hydrophilic contagion gown layer, hydrophobic controlled release clothing layer and enteric coating layer).This Pulsed drug delivery system is at enteral rapid solution and efficiently transport through biomembrane, can form pulse peak concentration, and bioavailability improves, and the pulse extended release time is 2 ~ 3 h, is mainly used in treatment person in middle and old age's property early awakening disease.
Summary of the invention
The invention provides delivery mode of the sleeping controlled release preparation of a kind of novel compound and preparation method thereof.Object is the deficiency filling up current hypnotic treatment effect.This compound controlled release sheet is used for the treatment of insomnia, can reach the double effects falling asleep and prevent early awakening fast after patient takes.
The present invention is the sleeping controlled release preparation of a kind of novel compound, containing two kinds of different active constituents of medicine (Active Pharmaceutical Ingredients, APIs).It is characterized in that, two kinds of active component successively releases.First time discharges API
1, 15 min releases>=80%; Second time discharges API
2, 0 ~ 2 h, release≤10%, 5 ~ 6 h release>=90%.
Novel controlled release sheet of the present invention, comprises the inner layer piece of band through hole, wraps in functional type coating outside inner layer piece and pastille outer shell.Described inner layer piece comprises active medicine and slow-release material, and described functional type coating comprises coating material, and described shell comprises another kind of active medicine.Compound controlled release preparation its consist of:
First release portion:
Rear release portion:
The preparation method of compound controlled release preparation is as follows: first press inner sustained-release layer sheet, then press immediate release outer layer sheet.
Accompanying drawing explanation
The structural representation of the sleeping controlled release preparation of this compound recipe of Fig. 1.
The In Vitro Dissolution curve (release-time) of Fig. 2 embodiment 1.
The In Vitro Dissolution curve (release-time) of Fig. 3 embodiment 2.
The In Vitro Dissolution curve (release-time) of Fig. 4 embodiment 3.
The In Vitro Dissolution curve (release-time) of Fig. 5 embodiment 4.
The In Vitro Dissolution curve (release-time) of Fig. 6 embodiment 5.
Mean blood plasma concentration-time graph in Fig. 7 embodiment 6 beasle dog body.
The In Vitro Dissolution curve (release-time) of Fig. 8 comparative example 1.
The drug disposition metabolism blood concentration-time curve of Fig. 9 comparative example 1.
The In Vitro Dissolution curve (release-time) of Figure 10 comparative example 2.
The In Vitro Dissolution curve (release-time) of Figure 11 comparative example 3.
Detailed description of the invention
Drug-eluting detection method in the present invention: according to Chinese Pharmacopoeia 2010 editions two annex XD drug release determination first methods (for slow release, controlled release, delayed release formulation), tablet is dropped in 900 mL 0.1 mol/L hydrochloric acid solutions, slurry processes, 50 rpm/min, 37 DEG C, draw appropriate dissolution fluid at regulation sample point and calculate tablet accumulative releasing degree, draw stripping curve.
Embodiment 1
The controlled release tablet of the present embodiment as shown in Figure 1, comprises inner layer piece and pastille shell, and inner layer piece is porose of a slow release layer.
Composition and the content of controlled release tablet are as follows: according to 1000 meters, every sheet weighs 450 mg.
Pastille shell:
Porose inner layer piece:
Preparation method:
1, inner layer piece supplementary material is weighed according to prescription, fully for subsequent use after mixing; Select the drift of two profiles number, No. I punch diameter is less than No. II;
2, use rotary tablet machine, install drift I, adjustment tablet machine depth of cracking closure and compression force, compacting inner layer piece, sheet is heavily every sheet 150 mg, inner layer piece hardness 80 N;
3, use rotary tablet machine, drift II is installed, adjustment tablet machine technological parameter, the inner layer piece suppressed first is placed on punch die central authorities, doses the coating material mixed, slugging, the bottom surface of inner layer piece and side are all covered, tablet gross weight 450 mg by coating material, hardness 100 N.
Detection of drugs stripping, stripping curve is shown in Fig. 2.As can be seen from Figure 2: controlled release tablet has twice release, a rapid release of shell and a slow release of inner layer piece is respectively.The Zolpidemtar Trate of first time release, 15 min releases >=90%; The Zolpidemtar Trate of second time release, 0 ~ 2 h, release≤10%, 5 ~ 6 h release >=80%.
In embodiment 1, controlled release tablet is made up of the inner layer piece containing Zolpidemtar Trate and the shell containing Zolpidemtar Trate, can reach the effect of twice release.And reproducible between 6 parallel tablets, RSD value < 2%.In embodiment 1, the drug model of preparation is suitable for chronic analgesic class and sleeping class medicine, and twice release can reach the object of fast onset and lasting effect.
Embodiment 2
The controlled release tablet of the present embodiment as shown in Figure 1, comprises inner layer piece and pastille shell, and inner layer piece is porose of a slow release layer.
Composition and the content of controlled release tablet are as follows: according to 1000 meters, every sheet weighs 450 mg.
Pastille shell:
Porose inner layer piece:
Preparation method:
1, inner layer piece supplementary material is weighed according to prescription, fully for subsequent use after mixing; Select the drift of two profiles number, No. I punch diameter is less than No. II;
2, use rotary tablet machine, install drift I, adjustment tablet machine depth of cracking closure and compression force, compacting inner layer piece, sheet is heavily every sheet 150 mg, inner layer piece hardness 80 N;
3, use rotary tablet machine, drift II is installed, adjustment tablet machine technological parameter, the inner layer piece suppressed first is placed on punch die central authorities, doses the coating material mixed, slugging, the bottom surface of inner layer piece and side are all covered, tablet gross weight 450 mg by coating material, hardness 100 N.
Detection of drugs stripping, stripping curve is shown in Fig. 3.As can be seen from Figure 3: controlled release tablet has twice release, a rapid release of shell and a slow release of inner layer piece is respectively.The Zolpidemtar Trate of first time release, 15 min releases >=80%; The Zolpidemtar Trate of second time release, 0 ~ 2 h, release≤10%, 5 ~ 6 h release >=80%.
In embodiment 2, controlled release tablet is made up of the inner layer piece containing Zolpidemtar Trate and the shell containing Zolpidemtar Trate, can reach the effect of twice release.In embodiment 2, the drug model of preparation is suitable for chronic analgesic class and sleeping class medicine, and twice release can reach the object of fast onset and lasting effect.
Embodiment 3
The controlled release tablet of the present embodiment as shown in Figure 1, comprises inner layer piece and pastille shell, and inner layer piece is porose of a slow release layer.
Composition and the content of controlled release tablet are as follows: according to 1000 meters, every sheet weighs 450 mg.
Pastille shell:
Porose inner layer piece:
Preparation method:
1, inner layer piece supplementary material is weighed according to prescription, fully for subsequent use after mixing; Select the drift of two profiles number, No. I punch diameter is less than No. II;
2, use rotary tablet machine, install drift I, adjustment tablet machine depth of cracking closure and compression force, compacting inner layer piece, sheet is heavily every sheet 150 mg, inner layer piece hardness 80 N;
3, use rotary tablet machine, drift II is installed, adjustment tablet machine technological parameter, the inner layer piece suppressed first is placed on punch die central authorities, doses the coating material mixed, slugging, the bottom surface of inner layer piece and side are all covered, tablet gross weight 450 mg by coating material, hardness 100 N.
Detection of drugs stripping, stripping curve is shown in Fig. 4.As can be seen from Figure 4: controlled release tablet has twice release, a rapid release of shell and a slow release of inner layer piece is respectively.The Zolpidemtar Trate of first time release, 15 min releases >=90%; The Zolpidemtar Trate of second time release, 0 ~ 2 h, release≤10%, 5 ~ 6 h release >=80%.
In embodiment 3, controlled release tablet is made up of the inner layer piece containing Zolpidemtar Trate and the shell containing Zolpidemtar Trate, can reach the effect of twice release.In embodiment 3, the drug model of preparation is suitable for chronic analgesic class and sleeping class medicine, and twice release can reach the object of fast onset and lasting effect.
Embodiment 4
The controlled release tablet of the present embodiment as shown in Figure 1, comprises inner layer piece and pastille shell, and inner layer piece is porose of a slow release layer.
Composition and the content of controlled release tablet are as follows: according to 1000 meters, every sheet weighs 450 mg.
Pastille shell:
Porose inner layer piece:
Preparation method:
1, inner layer piece supplementary material is weighed according to prescription, fully for subsequent use after mixing; Select the drift of two profiles number, No. I punch diameter is less than No. II;
2, use rotary tablet machine, install drift I, adjustment tablet machine depth of cracking closure and compression force, compacting inner layer piece, sheet is heavily every sheet 150 mg, inner layer piece hardness 80 N;
3, use rotary tablet machine, drift II is installed, adjustment tablet machine technological parameter, the inner layer piece suppressed first is placed on punch die central authorities, doses the coating material mixed, slugging, the bottom surface of inner layer piece and side are all covered, tablet gross weight 450 mg by coating material, hardness 100 N.
Detection of drugs stripping, stripping curve is shown in Fig. 5.As can be seen from Figure 5: controlled release tablet has twice release, a rapid release of shell and a slow release of inner layer piece is respectively.The Zolpidemtar Trate of first time release, 15 min releases >=90%; The Zolpidemtar Trate of second time release, 0 ~ 2 h, release≤10%, 5 ~ 6 h release >=80%.
In embodiment 4, controlled release tablet is made up of the inner layer piece containing Zolpidemtar Trate and the shell containing Zolpidemtar Trate, can reach the effect of twice release.In embodiment 4, the drug model of preparation is suitable for chronic analgesic class and sleeping class medicine, and twice release can reach the object of fast onset and lasting effect.
Embodiment 5
The controlled release tablet of the present embodiment as shown in Figure 1, comprises inner layer piece and pastille shell, and inner layer piece is porose of a slow release layer.
Composition and the content of controlled release tablet are as follows: according to 1000 meters, every sheet weighs 450 mg.
Pastille shell:
Porose inner layer piece:
Preparation method:
1, inner layer piece supplementary material is weighed according to prescription, fully for subsequent use after mixing; Select the drift of two profiles number, No. I punch diameter is less than No. II;
2, use rotary tablet machine, install drift I, adjustment tablet machine depth of cracking closure and compression force, compacting inner layer piece, sheet is heavily every sheet 150 mg, inner layer piece hardness 80 N;
3, use rotary tablet machine, drift II is installed, adjustment tablet machine technological parameter, the inner layer piece suppressed first is placed on punch die central authorities, doses the coating material mixed, slugging, the bottom surface of inner layer piece and side are all covered, tablet gross weight 450 mg by coating material, hardness 100 N.
Detection of drugs stripping, stripping curve is shown in Fig. 6.As can be seen from Figure 6: controlled release tablet has twice release, a rapid release of shell and a slow release of inner layer piece is respectively.The (+)-Zopiclone of first time release, 15 min releases >=90%; The Zolpidemtar Trate of second time release, 0 ~ 2 h, release≤10%, 5 ~ 6 h release >=90%.
In embodiment 5, controlled release tablet is made up of the inner layer piece containing (+)-Zopiclone and the shell containing Zolpidemtar Trate, can reach the effect of twice release.In embodiment 5, the drug model of preparation is suitable for chronic analgesic class and sleeping class medicine, and twice release can reach the object of fast onset and lasting effect.
Embodiment 6
Embodiment 1 is carried out animal pharmaceuticals metabolism.In this animal drugs generation, tests by China Medicine University's drug metabolism study Center and implements.
, laboratory animal information:
Animal subject is 2 beasle dogs, and Xin Gang laboratory animal field, Shanghai provides, animal credit number: SCXK(Shanghai) 2012-0009.Animal experiment part is carried out in Southeast China University's Experimental Animal Center, and this animal experimental center occupancy permit number is: SYXK(revives) 2010-0004.All animal subjects single sub-cage rearing, natural lighting, gives standard particle feedstuff and clean drinking-water.Administration the last fortnight to whole process of the test terminates not take any other medicine.
Table 1. laboratory animal information
| Number of animals | 1# | 2# |
| Sex | Male | Female |
| Body weight (kg) | 10.0 | 9.8 |
2, experimental technique:
The oral embodiment 1 of beasle dog, the dosage of every beasle dog is 11, with 30ml water delivery service during administration.
Blank blood is got before administration, after administration, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 36 h are from forelimb venous blood sampling 2.5 mL, in centrifugal 10 min of 4000 rpm, get blood plasma 1 mL, preserve for test for-20 DEG C.
, compound LC-MS/MS detection method
Mass Spectrometry Conditions
LC-MS/MS measures, and ion source is Turbo Spray source, spray voltage 5500V, and heated capillary temperature is 250 DEG C; Curtain gas is 20; GS1 is 20; GS2 is 20; CAD is 10; Bunch voltage is gone to be respectively 100V(zolpidem), mark in 114V(); Impact energy (CE) is respectively 48eV(zolpidem), mark in 30eV().Scan mode is reaction of high order monitoring (MRM), and the ionic reaction for quantitative analysis is respectively m/z 308.1 → 235.0(zolpidem), mark in m/z 285.3 → 154(, diazepam).
3.2 chromatographic condition
Chromatographic column: Hedera, 150 × 2.1 mm, 5 μm of Ser.No:C981210513; Column temperature 40 DEG C; Mobile phase A is aqueous phase, and Mobile phase B is acetonitrile, gradient elution 0 ~ 0.6 min, B 10%; 0.6 ~ 2.1 min, B 80%; 2.1 ~ 3.5 min, B 80%; 3.5 ~ 5.50 min, B 10%; 5.5 ~ 6.5 min, B 10%, 6.50 stop.Flow velocity is 0.35 mL/min.
sample treatment
From-20 DEG C of refrigerators, take out plasma sample, at room temperature naturally melt.After blood plasma melts completely, by plasma sample vortex 30 s on vortex instrument, get plasma sample 50 μ L in test tube, add 100 μ L acetonitriles and the 50 μ L acetonitrile containing mark (diazepam) in 50 ng/mL, shake 3 min, in centrifugal 10 min of 16000 rpm, get supernatant 10 μ L sample introduction, measure the blood drug level of zolpidem.
The computational methods of 3.4 pharmacokinetic parameters:
DAS 2.0 pharmacokinetics professional software, carries out computing with statistical moment method, tries to achieve every corresponding pharmacokinetic parameters of animal.
, experimental result
Determination of plasma concentration
4.1.1 after gavage gives beasle dog embodiment 1, in body, zolpidem determination of plasma concentration the results are shown in Table 2.
Table 2 gavage gives zolpidem blood drug level (ng/ml) in the rear body of beasle dog embodiment 1
| Time(h) | Dog1 | Dog2 | Mean |
| 0 | 0 | 0 | 0 |
| 0.5 | 3.63 | 12 | 7.815 |
| 1 | 5.69 | 8.79 | 7.240 |
| 2 | 2.6 | 2.16 | 2.380 |
| 3 | 2.51 | 1.61 | 2.060 |
| 4 | 3.37 | 1.26 | 2.315 |
| 5 | 0.84 | 1.04 | 0.940 |
| 6 | 0.859 | 0.756 | 0.808 |
| 7 | 0.926 | 0.935 | 0.931 |
| 8 | 0.888 | 0.614 | 0.751 |
| 10 | 0.994 | 0.786 | 0.890 |
| 12 | 0.812 | 0.831 | 0.822 |
| 24 | 0.431 | 0.378 | 0.405 |
| 36 | 1.12 | 0.679 | 0.900 |
In body after 2 dogs take the embodiment of the present invention 1, average blood medicine-time-concentration curve is shown in Fig. 7.
Medicine moves parameter
4.2.1 after gavage gives the beasle dog embodiment of the present invention 1, in body, zolpidem determination of plasma concentration the results are shown in Table 3.
Table 3 is oral gives embodiment 1 the rear pharmacokinetic parameter of zolpidem in beasle dog body
5, experiment conclusion
Can observe after beasle dog gavage gives embodiment 1 in this experiment, the AUC of two beasle dogs, T
1/2, CL
zparameter is moved substantially identical Deng medicine, by making the dynamic characteristic of graph discovery model drug zolpidem in two beasle dog bodies be: after beasle dog gavage, mean blood plasma concentration curve occurs bimodal, infers that likely embodiment 1 occurs bimodal due to the rapid release of preparation and slow release effect in beasle dog body.
Comparative example 1 is the embodiment 3 in patent US 6514531 B1, and it is Zolpidem tartrate controlled-release sheet (AMBIEN CR) formulation patent.Said preparation is comprise the release layer containing Zolpidemtar Trate and the slow release layer containing Zolpidemtar Trate.The In Vitro Dissolution curve of said preparation is shown in Fig. 8, and its feature is similar to embodiment 1.But as can be seen from drug disposition metabolism blood concentration-time curve (Fig. 7, Fig. 9), embodiment 1 is compared with the outstanding advantages of comparative example 1, also can reach the effect of twice release in vivo.
Comparative example 2
Buy commercially available Zolpidem Tartrate (Stilnox, Sai Nuofei (Hangzhou) pharmaceutical Co. Ltd), get 6 and do stripping detection, average and draw In Vitro Dissolution curve, the results are shown in Figure 10.
As can be seen from Fig. 2 and Figure 10 contrast, the more commercially available Zolpidemtar Trate ordinary tablet of embodiment 1 has significant advantage---there is twice release: first time discharges fast, can make active component quick acting; Second time slow releasing makes active component sustained release.6(Fig. 8 in conjunction with the embodiments) known, embodiment 1 and comparative example 2 contrast, and can reach the double effects falling asleep and prevent early awakening fast.
Comparative example 3
Buy commercially available (+)-Zopiclone sheet (Wen Fei, Tianshili Diyi Pharmaceutical Ind Co., Ltd., Jiangsu), get 6 and do stripping detection, average and draw In Vitro Dissolution curve, the results are shown in Figure 11.
Found out by Figure 11, release is complete fast in 15 min for comparative example 3.Compare with embodiment 5, although (+)-Zopiclone is all quick release, the slow releasing of one more Zolpidemtar Trate after 2 h in embodiment 5.Therefore can reach twice release, thus play the object of fast onset and lasting effect.
Claims (10)
1. the sleeping controlled release preparation of compound recipe, controlled release preparation is interior surrounding layer sheet, it is characterized in that the porose or atresia of inner layer piece.
2., according to claim 1, said preparation internal layer is porose.
3. according to claim 1, said preparation contains two kinds of active constituents of medicine, it is characterized in that, two kinds of active component successively releases, and first time discharges API1,15 min releases >=60%; Second time discharges API2,0 ~ 2 h, release≤20%, 3 ~ 6 h release >=80%.
4. according to claim 1, first time discharges API1,15 min releases >=60%; Second time discharges API2,0 ~ 2 h, release≤20%, 4 ~ 6 h release >=80%.
5. according to claim 1, first time discharges API1,15 min releases >=60%; Second time discharges API2,0 ~ 2 h, release≤20%, 5 ~ 6 h release >=80%.
6. according to claim 1, compound controlled release preparation its consist of:
First release portion:
Rear release portion:
According to claim 1, the preparation method of compound controlled release preparation is as follows: first pressure debugging inner layer piece, enteric coated, then presses immediate release outer layer sheet.
7., according to claim 1, the present invention is used for the treatment of the symptom that insomnia adds early awakening.
8., after taking, patient can be allowed to fall asleep fast, and prevent patient's early awakening.
9., according to claim 6, the present invention, except treatment early awakening, can also treat " being still drank after a night " phenomenon of the next morning.
10. according to claim 1, active constituents of medicine API1 and API2 in the present invention can be different medicines, also can be same medicine.
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