A kind of sustained release tablets and preparation method thereof of hydrochloric TrazodoneTechnical field
The present invention relates to the sustained release tablets and its preparation side of pharmaceutical technology field more particularly to a kind of hydrochloric TrazodoneMethod.
Background technique
Trazodone (Trazodone) is artificial synthesized novel triazole pyridines antidepressants, is belonged to serotonin (5-HT)Beta blocker and reuptaking inhibitor have apparent maincenter sedation and slight myorelaxant effects.
Trazodone hydrochloride is white to off-white color crystallization or crystalline powder；Light is met to be not sufficiently stable.Its chemical name is 2-[3- [4- (3- chlorphenyl) -1- piperazinyl] propyl] -1,2,4- triazols [4,3-a] pyridine -3 (2H) -one mono-hydrochloric salts, structureFormula is as follows.
Trazodone hydrochloride be serotonin (5-HT) beta blocker and reuptaking inhibitor, 1972 Italy firstListing is a kind of antidepressant efficiently, safe, in multiple countries for light, moderate depressive patients treatment.
The study found that trazodone hydrochloride ordinary tablet is usually prescribed one day administered twice or instant-free form three times,The administration of dosage in this way, which frequently can lead to the drug in blood, cannot maintain in so-called therapeutic window, thus, when reachingWhen blood concentration high level, it is possible to create the high risk with dosage related side effects is in when reaching blood concentration low-levelExisting lower curative effect, in addition, administration is easy to cause in one day the multiple blood medicine peak phase to several sleepiness week occur for multiple dailyPhase.
Compared with conventional tablet, trazodone hydrochloride sustained release tablets only need to take medicine daily once, and Trazodone can be made very one section longIt is steadily discharged in time, maintains effective Trazodone blood concentration in a longer period of time, and its release behavior does not depend on pH, thisSample Trazodone can reduce the frequency of the side effect of daytime drowsiness substantially in the top and the bottom of entire gastrointestinal tract by uniform pickupRate and severity.
CN101252932 is provided at the trazodone hydrochloride sustained release tablets (Oleptro) of ANGELINI production of U.S.'s listingSide and preparation process, mainly using sustained release excipient hydroxypropyl two form sediment sour powder phosphide (trade name Contramid) and on a small quantity bondThe materials such as agent hydroxypropyl methylcellulose control the release of drug.Its used hydroxypropyl two sour current country of powder phosphide of forming sediment there is noPharmaceutical grade is other to be can be used, and this auxiliary material is by patent protection, in addition this listing product the intestinal environment higher than pH6.8 discharge compared withIt is low, it discharges for 24 hours not enough thoroughly, to avoid being likely to occur cumulative appearance, therefore the space that still has some improvement.
102935074 A of CN provides a kind of trazodone hydrochloride disclosed in Chengdu Kanghong Medicine Group Co.ltdThe preparation method of osmotic pump controlled release tablet, controlled release tablet include tablet core, semi-transparent film coating and release hole three parts composition, preparationTechnique is relative complex and preparation process is very high to the outfit of equipment and performance requirement, while the accuracy pair that its preparation process requiresThe realization difficulty of industrialization is larger, and drug quality is more inhomogenous, and reproducibility is poor, and the industrialization for being unfavorable for slow controlled release drug pushes awayExtensively.
Therefore, the prior art is defective, needs to improve.
Summary of the invention
The technical problems to be solved by the present invention are: providing, a kind of prescription is simple and simple process, can be in certain timeInterior stabilization, sustained release trazodone hydrochloride, held stationary, effective blood concentration hydrochloric Trazodone sustained release tablets and its systemPreparation Method.
Technical scheme is as follows: a kind of sustained release tablets of hydrochloric Trazodone, including the total slice weight 15%~65% of ZhanTrazodone hydrochloride, the total slice weight 30%~85% of Zhan sustained-release matrix and the total slice weight of Zhan 0.1~10% it is other medicinal auxiliaryMaterial；Wherein, sustained-release matrix is made of high viscosity hydroxypropyl methylcellulose and water-soluble filler, high viscosity hydroxypropyl methylcellulose and waterWeight ratio is 1:0.3~1.2 between soluble filler；Other pharmaceutic adjuvants include glidant and lubricant.
Applied to above-mentioned technical proposal, in the sustained release tablets, the raw material particle size of trazodone hydrochloride is 30 mesh~150 mesh；Alternatively, its preferred raw material partial size is 60 mesh~100 mesh.
Applied to above-mentioned technical proposal, in the sustained release tablets, high viscosity hydroxypropyl methylcellulose is selected from hydroxypropyl methylcelluloseK100M, also, weight ratio is 1:0.45~0.55 or 1:0.75 between high viscosity hydroxypropyl methylcellulose and water-soluble filler~1.
Applied to above-mentioned technical proposal, in the sustained release tablets, water-soluble filler is lactose, sucrose, mannitol, fructoseIn it is one or any several.
Applied to above-mentioned technical proposal, in the sustained release tablets, high viscosity hydroxypropyl methylcellulose is that vertical compression type hydroxypropyl first is fineElement K100M is tieed up, raw material particle size is 60 mesh~100 mesh, and water-soluble filler is lactose, and raw material particle size is 80 mesh~100 mesh.
Applied to above-mentioned technical proposal, in the sustained release tablets, the percentage of the total slice weight of trazodone hydrochloride Zhan is 27.73%Or 49.02%, the percentage of the total slice weight of lactose Zhan is 20%~25%.
Applied to above-mentioned technical proposal, in the sustained release tablets, glidant is silica, superfine silica gel powder, talcum powder, tenOne of sodium dialkyl sulfate is any several；Lubricant is magnesium stearate, Compritol 888 ATO, PEG4000 or criticizesOne of pEG6000 or any is several.
Applied to above-mentioned technical proposal, the preparation method of the sustained release tablets of more than one hydrochloric Trazodones, including stepIt is rapid: A: trazodone hydrochloride, high viscosity hydroxypropyl methylcellulose, water-soluble filler being mixed；B: after glidant and lubricant is addedTabletting after mixing；C: coating obtains the sustained release tablets of hydrochloric Trazodone.
Applied to above-mentioned technical proposal, in the preparation method, in step B, glidant is added and mix lubricant is equalIt is that direct tablet compressing is carried out to mixture using powder vertical compression technique after even.
Applied to above-mentioned technical proposal, in the preparation method, after step A, also in trazodone hydrochloride, high viscosity hydroxylAdhesive is added in third methylcellulose, water soluble bulk agent composition and pelletizes, then, executes step B after being dried again.
Using the above scheme, the present invention is used cooperatively by using high viscosity hydroxypropyl methylcellulose and water-soluble filler,It is formed and has micro porous sustained-release matrix；It is slower that high viscosity hydroxypropyl methylcellulose forms hydrated gel interval velocity in water, can growTime maintains trazodone hydrochloride slow release, allows to stable, sustained release trazodone hydrochloride within a certain period of time, keeps flatSurely, effective blood concentration；Water-soluble filler can dissolve to form drug release channel in water, and control suitable proportion dosage can be withIt is effectively prevent phenomenon of burst release, patient is enable to guarantee effective blood concentration at medication initial stage；Therefore, salt love song prepared therefromOxazolone sustained release tablets can be effectively controlled trazodone hydrochloride rate of release again and can make in sustained release label contained trazodone hydrochloride certainIt is discharged completely in time, so that water-soluble trazodone hydrochloride be made to be easy to steady, be released effectively, blood concentration is avoided to generate substantiallyDegree fluctuation, prescription is simple and simple process.
Detailed description of the invention
Fig. 1 is that case study on implementation and original grind sustained release tablets and dissolve out release profiles in aqueous medium；
Fig. 2 is that case study on implementation and original grind sustained release tablets and dissolve out release profiles in pbs6.8 phosphate-buffered liquid medium；
Fig. 3 is that case study on implementation and original grind sustained release tablets and dissolve out release profiles in pH4.5 acetate salt buffer liquid medium；
Fig. 4 is that case study on implementation and original grind sustained release tablets and dissolve out release profiles in pH1.2 hydrochloric acid solution medium.
Specific embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.
A kind of sustained release tablets of hydrochloric Trazodone are present embodiments provided, the present embodiment is for the same kind of existing patentSlow, controlled release tablet deficiency provides that a kind of prescription is simple and the trazodone hydrochloride sustained release tablets of simple process, should be dynamic in medicine from film-makingThe release in research with more steady blood concentration is learned, and is able to achieve release completely in vivo for 24 hours.
The trazodone hydrochloride sustained release tablets of the present embodiment contain trazodone hydrochloride, high viscosity HPMC, i.e. high viscosity hydroxypropyl first is fineDimension element, water-soluble filler, also contain other pharmaceutic adjuvants.Wherein, the total slice weight of trazodone hydrochloride Zhan is 15%~65%, hydrochloric acidThe total slice weight of Trazodone Zhan is preferably 27.73% or 49.02%, high viscosity hydroxypropyl methylcellulose and water-soluble filler composition sustained releaseSkeleton, the 30%~85% of the total slice weight of the total Zhan of sustained-release matrix, the 0.1~10% of other total slice weights of pharmaceutic adjuvant Zhan, sustained-release matrixWeight ratio is about 1:0.3~1.2, high viscosity hydroxypropyl methylcellulose between middle high viscosity hydroxypropyl methylcellulose and water-soluble fillerIt is preferably 1:0.45~0.55 or 1:0.75~1 with water-soluble filler, other pharmaceutic adjuvants are mainly by glidant and lubricationAgent composition.
In this way, being used cooperatively by using full-bodied HPMC and water-soluble filler, is formed and have micro porous sustained releaseSkeleton, contained by trazodone hydrochloride sustained release tablets prepared therefrom can be effectively controlled trazodone hydrochloride rate of release again and can make in labelTrazodone hydrochloride discharges completely within a certain period of time, so that water-soluble trazodone hydrochloride be made to be easy to steady, be released effectively, avoidsBlood concentration generation is fluctuated widely.
Wherein, high viscosity hydroxypropyl methylcellulose can be selected from hydroxypropyl methylcellulose K100M, HPMC K4M, hydroxypropylMethylcellulose K15M, experimentation discovery, hydroxypropyl methylcellulose viscosity is bigger, and slow release effect is opposite to be more obvious, usage amount phaseIt, as a result, can preferably hydroxypropyl methylcellulose K100M according to dissolution to fewer.
Water-soluble filler can be selected from the one or more of them such as lactose, sucrose, mannitol, fructose and be used in combination, according toMaterial dissolution performance and compressibility can preferred lactose.Experimentation uses raw material particle size for 100 mesh vertical compression lactose, and drug release process is slowSlowly, orderly and stable.
It is slower that high viscosity hydroxypropyl methylcellulose forms hydrated gel interval velocity in water, can maintain trazodone hydrochloride for a long timeSlow release allows to stable, sustained release trazodone hydrochloride within a certain period of time, held stationary, effective blood concentration.Water-soluble filler can dissolve to form drug release channel in water, and phenomenon of burst release can be effectively prevented in control suitable proportion dosage,Patient is set to guarantee effective blood concentration at medication initial stage.
Also, the trazodone hydrochloride sustained release tablets of the present embodiment also contain other pharmaceutic adjuvants, mainly contain glidant and profitLubrication prescription, also optionally containing adhesive etc..It is preferred that vertical compression technique, other pharmaceutic adjuvants are then mainly by glidant and lubricantComposition.Glidant can be selected from the collocation of the one or more of them such as silica, superfine silica gel powder, talcum powder, lauryl sodium sulfateIt uses, lubricant can be selected from the one or more of them collocation such as magnesium stearate, Compritol 888 ATO, PEG4000 or crowd pEG6000It uses.According to wet granulation technology, adhesive can be selected from water, ethanol water, PVP K30, sodium carboxymethylcellulose etc.One or more of them collocation uses.
The trazodone hydrochloride sustained release tablets of the present embodiment can be coated, coating agent dosage be total slice weight 0.1%~10%, coating agent is preferably color coat powder.
In one preferred embodiment of the present embodiment, high viscosity hydroxypropyl methylcellulose in the sustained release tablets of hydrochloric TrazodoneSelected from hydroxypropyl methylcellulose K100M, water-soluble filler is selected from lactose, wherein the total slice weight of trazodone hydrochloride Zhan 27.726%,The total slice weight of hydroxypropyl methylcellulose K100M Zhan 45.287%, the total slice weight of lactose Zhan 24.954%.
In second preferred embodiment of the present embodiment, high viscosity hydroxypropyl methylcellulose is selected in trazodone hydrochloride sustained release tabletsFrom hydroxypropyl methylcellulose K100M, water-soluble filler is selected from lactose, wherein the total slice weight of trazodone hydrochloride Zhan 49.02%, hydroxypropylThe total slice weight of methylcellulose K100M Zhan 27.78%, the total slice weight of lactose Zhan 21.242%.
In another preferred embodiment of the present invention, high viscosity hydroxypropyl methylcellulose is selected from trazodone hydrochloride sustained release tabletsHydroxypropyl methylcellulose K100M, water-soluble filler are selected from lactose, and wherein the total slice weight 49.02% of trazodone hydrochloride Zhan, hydroxypropyl first are fineTie up the total slice weight 25.33% of element K100M Zhan, the total slice weight 23.69% of lactose Zhan.
In another preferred embodiment of the present embodiment, high viscosity hydroxypropyl methylcellulose is selected in trazodone hydrochloride sustained release tabletsFrom hydroxypropyl methylcellulose K100M, water-soluble filler is selected from lactose, wherein the total slice weight of trazodone hydrochloride Zhan 27.727%, hydroxylThe third total slice weight of methylcellulose K100M Zhan 48.06%, the total slice weight of lactose Zhan 22.18%.
The amount of trazodone hydrochloride refers to the amount of trazodone hydrochloride sterling in the present embodiment, can be according to moisture, content through rolling over waterPure to be calculated, the pure calculation method of folding water is known to the skilled person.
In the present embodiment " total slice weight " refer to without coating agent or it is uncoated when total weight of tablet.
The present embodiment additionally provides the preparation method of trazodone hydrochloride sustained release tablets.Method one: by trazodone hydrochloride, high viscosityHydroxypropyl methylcellulose, water-soluble filler mixing, add after glidant and lubricant and are uniformly mixed direct tablet compressing, are coated to obtain the final productThe sustained release tablets of hydrochloric Trazodone.Method two: trazodone hydrochloride, high viscosity hydroxypropyl methylcellulose, water-soluble filler are mixedAdhesive granulation is added, adds glidant after dry and mix lubricant is uniform, tabletting, coating obtains saliferous love song azolesThe sustained release tablets of ketone.
It is used cooperatively in the present embodiment using full-bodied slow-release material and water-soluble filler, especially high viscosityHPMC forms if hydroxypropyl methylcellulose K100M and lactose are used cooperatively and has micro porous sustained-release matrix, reach i.e. effective controlTrazodone hydrochloride rate of release processed can make the effect that contained trazodone hydrochloride discharges completely within a certain period of time in label again.AndThe trazodone hydrochloride sustained release tablets of the present embodiment can be covered with color coat, have more preferably stability compared with plain piece.
The sustained release tablets Oleptro of hydrochloric Trazodone mainly uses sustained release excipient hydroxypropyl two to form sediment sour powder phosphide, commodityThe materials such as name Contramid, a small amount of adhesive hydroxypropyl methylcellulose and sodium stearyl fumarate control the release of drug, using notIt is same as the former slow-released system for grinding medicine, obtains grinding medicine Oleptro than original, discharges more stable and more thorough slow release effect, according to formerThe clinical use effect of medicine Oleptro is ground, it can be achieved that 24 hours blood medicines continue the concentration of slow release.Through quality research and stabilizationProperty investigate, it is more excellent that the present embodiment product than original grinds the intracorporal release of medicine Oleptro24h, and quality stability is more preferably, and product hasClose the attributes such as substance and content ground with original it is substantially consistent, this for the present embodiment products substitution original grind medicine conduct clinic first choice providePossibility.Simultaneously preparation process preferred powder vertical compression technique of the present invention, it is easy to operate, be easy to amplify metaplasia produce, and cost compared withIt is low, advantageously reduce product price.
The following are specific prescription embodiments:
Embodiment 1
Prescription
Preparation process:
It weighs recipe quantity trazodone hydrochloride, hydroxypropyl methylcellulose K100M, vertical compression lactose to be pre-mixed, adds dioxySiClx and magnesium stearate are uniformly mixed.
Tabletting.
Coating: it takes the coloured film coating agent of recipe quantity to be configured to 10% full water coating solution and is coated.
Embodiment 2
Prescription
Preparation process:
It weighs recipe quantity trazodone hydrochloride, hydroxypropyl methylcellulose K100M, vertical compression lactose to be pre-mixed, adds dioxySiClx and magnesium stearate are uniformly mixed.
Tabletting.
Coating: it takes the coloured film coating agent of recipe quantity to be configured to 10% full water coating solution and is coated.
Embodiment 3
Prescription
Preparation process:
It weighs recipe quantity trazodone hydrochloride, hydroxypropyl methylcellulose (K100M) and lactose to be pre-mixed, adds 80%Ethanol solution adhesive carries out the granulation of 30 mesh of wet process, then 55 ± 5 DEG C of dryings carry out 30 mesh whole grains again.Be added silica andMagnesium stearate is uniformly mixed.
Tabletting.
Coating: it takes the coloured film coating agent of recipe quantity to be configured to 10% full water coating solution and is coated.
Embodiment 4
Prescription
Preparation process
It weighs recipe quantity trazodone hydrochloride, hydroxypropyl methylcellulose (K100M) and lactose to be pre-mixed, adds 80%Ethanol solution adhesive carries out the granulation of 30 mesh of wet process, then 55 ± 5 DEG C of dryings carry out 30 mesh whole grains again.Be added silica andMagnesium stearate is uniformly mixed.
Tabletting.
Coating: it takes the coloured film coating agent of recipe quantity to be configured to 10% full water coating solution and is coated.
Drug release determination
It is carried out according to the trazodone hydrochloride sustained release tablets Oleptro that patent original grinds patent CN101252932 and U.S.'s listingIn vitro for 24 hours dissolved corrosion study, and with self-control sample, i.e., embodiment 1-4 prescription prepare, release behavior is compared.MeasurementMethod: taking this product, according to drug release determination method (0931 dissolution rate and drug release determination under the four general rule items of version Chinese Pharmacopoeia in 2015Method, the second method) operation, respectively at 1,2,3,6,8,12,10ml is sampled for 24 hours, is filtered through 0.45 μm of miillpore filter, is discarded initial filterLiquid, takes subsequent filtrate spare, adds synthermal, the respective media of same volume in time, and subsequent filtrate is measured absorbance at 311nm,Different time sample liquid concentration is calculated according to standard curve, 24 hours Cumulative release amounts and the relationships of time are investigated, notReleasing curve diagram with medium is as shown in Figs 1-4.The vitro release of trazodone hydrochloride sustained release tablets provided in this embodiment according toOriginal grinds In Vitro Dissolution data of sustained release tablets under the conditions of same media and dissolving-out method and determines that this product 1h release is not in an aqueous mediumGreater than the accumulative release of 30%, 6h in the accumulative release of 30~55%, 12h less than 80%, 80% should be not less than by adding up release for 24 hours.
The above is merely preferred embodiments of the present invention, be not intended to restrict the invention, it is all in spirit of the invention andMade any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within principle.