CN101953822B - Venlafaxine hydrochloride controlled release tablets and preparation method thereof - Google Patents
Venlafaxine hydrochloride controlled release tablets and preparation method thereof Download PDFInfo
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Abstract
The invention discloses venlafaxine hydrochloride controlled release tablets and a preparation method thereof. The venlafaxine hydrochloride controlled release tablets are elementary osmotic pump (EOP) controlled release tablets which comprise single-layer tablet cores, insoluble semi-permeable membranes and medicament release holes. In the invention, the high-molecular-weight ethylene oxide, microcrystalline cellulose and sodium chloride three auxiliary materials mixed in a proper ratio form a balance system for medicament dissolution and osmotic pressure generation in a pump chamber, and tablet weight is adjusted by using detrix as a filler, so that a high-medicament-capacity osmotic pump preparation can be obtained and the stable and lasting release can be kept. The preparation effectively overcome the shortcomings that the conventional sustained-release preparation is limited in the stability and controllability of the medicament release and can generate stable and constant-speed release, and the medicament release is protected from the influences of stomach and intestine environments, so that individual difference is reduced and the medicament controlled release design aim of giving play to curing effects and reducing side effects is further fulfilled.
Description
Technical field
The present invention relates to the VENLAFAXINE HCL controlled release preparation, be specifically related to a kind of oral hydrochloride venlafaxine osmotic pump controlled release tablet and preparation method thereof.
Background technology
Venlafaxine is a kind of 5-hydroxy tryptamine (5-HT) and the two recovery blockeres of norepinephrine (NE) by U.S. Wyeth exploitation, clinically is used to treat depression and generalized anxiety disorder.Depression influences people's life more and more widely as " by-product " of modern economy high speed development.Have data to show that the people of China 70% is in sub-health state, the disease patient relevant with psychology accounts for crowd's 5%～10%, and mental disease and mental maladjustment have become frequently-occurring disease, commonly encountered diseases." World Health Report " that The World Health Organization (WHO) delivers shows that depression has become the fourth-largest illness in the world, possibly become to the year two thousand twenty depression to be only second to cardiopathic second largest disease.
1997; Wyeth has developed venlafaxine hydrochloride sustained-release capsule (trade name Efexor XR) on its common delivery formulations basis; Realized taking medicine once a day, patient's compliance is better and the higher effect of clinical cure rate, a few years promptly becomes one of maximum antidepressant product of global recipe quantity.Yet as known, there is restriction in slow releasing preparation aspect the stationarity of drug release and controllability, be difficult to form stable constant release, and drug release is influenced by gastroenteric environment and uncertain.In addition, the drug release of slow releasing preparation is very big at interindividual variation usually.The difficulty that the problems referred to above of slow releasing preparation cause the doctor that patient's medication is grasped, more serious, the medicament slow release purpose of design that might be able to not realize bringing into play curative effect, reduces side effect.
Osmotic pump preparation is a kind of controlled release preparation of generally acknowledging at present; Rely on osmotic pressure and produce release power initiatively; The release mechanism slow releasing preparation that limit drug discharges with depending on environmental factors such as diffusion and/or corrosion has the difference of essence, has effectively overcome the existing problem of aforementioned slow releasing preparation.Therefore, osmotic pumps technology the clinical benefit that can produce also attracted much human this technology to be applied to the exploitation of VENLAFAXINE HCL.
VENLAFAXINE HCL has good water-solubility and intestinal absorption characteristic, this make those skilled in the art's first-selection with this drug design be primary osmotic pump (Elementary Osmotic pump, EOP).In fact, the Osmotica drugmaker that is positioned at U.S. Phoenix city has just developed the VENLAFAXINE HCL osmotic pump preparation of EOP structure in the nineties, and successfully goes on the market in countries such as South America in 1999.Domestic; The document of patent No. ZL200410090656.3 discloses a kind of EOP structure VENLAFAXINE HCL osmotic pump preparation and preparation method thereof; The said medicine label of this patent has comprised osmotic pressure promoter, filler, binding agent and lubricant; Its structure and method for preparing all are techniques well known, and relate to most adjuvants (" novel form of medicine and new technique ", the Lu Bin all on the books in existing document or textbook that possesses above-mentioned effect in this patent; The People's Health Publisher, March in 1998 the 1st edition; July in 2005 the 2nd edition).Such as we knowledge; EOP structure osmotic pump preparation will reach expection and discharge design; On prescription, many problems that will solve and overcome are arranged, its key is, need the rate of dissolution of medicine be allocated in appropriate scope; And in dispose procedure, can keep the osmotic pressure that matches; Be that the size of osmotic pressure and the rate of dissolution of keeping this osmotic pressure active substance become key factor equally, discharge too fastly or slow excessively, perhaps descend because of the not enough drug release rate that causes of osmotic pressure that discharges the later stage otherwise all can produce.Yet different drug has different dissolubility and rate of dissolution, and being label with environment of living in, other compositions are relevant; And also there is identical problem in different osmotic pressure active substances, except that dissolubility and rate of dissolution are influenced each other, also can cause the change of osmotic pressure in the system with the compatibility of other label compositions or even ingredient.Therefore, the osmotic pumps characteristics of EOP structure have determined to obtain versatile formulation, also can not be with well known auxiliaries arbitrarily and/or the drug release that just can obtain to set in the wide range collocation.
The venlafaxine hydrochloride sustained-release capsule of Hui Shi has two kinds of specifications, is respectively 75mg and 150mg (in venlafaxine).For the 150mg specification, the weight ratio of label medicine and adjuvant surpasses 75: 125, makes the nearly 500mg of total sheet reclosing, and label is oversize, not only can cause patient's dysphagia, and the large scale label causes that friability increases, and causes difficulty to the release-controlled film coating.Because it is that the release-controlled film material carries out the organic solvent coating that osmotic pump preparation needs the cellulose acetate with costliness, and will reach high relatively film thickness, the organic solvent consumption is big, and coating is long man-hour, will cause very big cost to increase if label is oversize.In addition; Existing research shows; The holdup time of preparation in gastrointestinal tract is relevant with its size, and for the preparation that is kept perfectly in this gastrointestinal tract of osmotic pump tablet, the big more producible holdup time individual variation of size is big more; Mean that blood drug level difference is big more in the producible body, promptly reducing tablet sizes also is favourable for reducing individual variation.
Application number is that 200610140521.2 patent application discloses a kind of VENLAFAXINE HCL osmotic pumps method for preparing that need not laser boring, forms the duct by soluble material in the release-controlled film (porogen) dissolving back, and medicine is through these ducts release.We discover, when osmotic pump preparation when not perforate of surface (laser or mechanical hole), the inside and outside osmotic pressure of pump chamber can cause volume and increase and make release-controlled film generation deformation, film rupture takes place easily cause medicine and come down in torrents.Concurrent deformation also makes the duct that the release-controlled film phase not of producing has, and causes the uncertain of drug release.For reducing this influence, need the very thick release-controlled film clothing of bag usually to increase film clothing mechanical strength and rigidity.As previously mentioned, the increase of release-controlled film clothing can bring very large production cost.In addition, the initial drug release of this atresia osmotic pumps has very big " time-lag effect ", and promptly initial release is very slow, and the thickness increase further increases the weight of this " time-lag effect ".Although can increase a part of medicine release layer with the coating mode and reduce " time lag ",, on quantitatively, be very difficult to control with coating mode medicine carrying for commercial production as this patent is described.Because the coating solution that has atomized in the coating process also can be by a lot " film " materials of carried away by air movement with solvent evaporates the time; These losses are relevant with ventilation and atmospheric environment (temperature, humidity, air pressure etc.); And we know; Atmospheric environment is almost all changing every day, and this also causes the loss of pastille composition in " film " material to change.
The commercial Application technology of laser is very ripe and general, and the special-purpose laser drilling device of our osmotic pump preparation successfully is used for the suitability for industrialized production several years, and unit speed can reach 9 slices/second, and application cost is very cheap.For the prior art condition, select the perforation structure osmotic pump tablet all to have very strong advantage from cost and quality control aspect.Yet, say like the front, must solve the low excessively drug loading amount problem of prior art.
Summary of the invention
The object of the invention just provides a kind of VENLAFAXINE HCL controlled release preparation; Adopt the osmotic pumps technology of laser boring to realize the VENLAFAXINE HCL controlled release drug administration; Drug action is long, only take once every day, keeps steady blood drug level and at utmost reduces drug side effect.
Another object of the present invention provides a kind of method for preparing of VENLAFAXINE HCL controlled releasing penetrant pump of high drug loading amount, and with the label weight percent meter, the drug loading amount can be greater than 50%.For osmotic pump preparation, improve the drug loading amount, not only make things convenient for the patient to swallow and carry, be easier to production control and avoid release-controlled film coating production cost to increase considerably.
The present invention is based on that following our result of study realizes.Our result of study is found, for the osmotic pump preparation of EOP structure, with VENLAFAXINE HCL and HMW polyethylene glycol oxide (POLYOX
TMSeries, Dow Chemical Company) compatibility, can produce beyond thought effect: (1) a spot of polyethylene glycol oxide can obviously suppress the rate of dissolution of VENLAFAXINE HCL, helps the lasting release of the indoor VENLAFAXINE HCL of osmotic pumps; (2) polyethylene glycol oxide has inhibition to the rate of dissolution of the osmotic pressure active substance sodium chloride that the most often uses in the osmotic pump preparation equally, is pressed with better effect for discharging the enough infiltrations of later stage holding pump indoor and outdoor; (3) although polyethylene glycol oxide has inhibition to the rate of dissolution of VENLAFAXINE HCL; But do not reduce the initial drug rate of release; On the contrary; Its suction " swelling " effect quickened initial drug release, drug release " time lag " effect that produces because of initial " hydration process " that has reduced that osmotic pump preparation has usually, thus make the linearity of medicine release profiles better; (4) the polyethylene glycol oxide consumption of the above-mentioned effect of generation is relevant with its molecular weight size, and molecular weight is big more, and consumption is few more.
Our research finds that also microcrystalline Cellulose also can produce the effect that suppresses VENLAFAXINE HCL and sodium chloride rate of dissolution, but wants weak a lot of with respect to polyethylene glycol oxide.Because both adhere to separately insoluble and water-soluble high-molecular compound, infer that both suppress the mechanism of action of water soluble drug and inequality.Yet, in EOP structure osmotic pumps with both simultaneously compatibilities use, can produce beyond thought result equally: (1) has synergistic effect although mechanism of action is different after share, and with respect to the effect of any single component increase is arranged all, promptly consumption can reduce; (2) the insoluble characteristic of microcrystalline Cellulose water enables in pump chamber, to play certain " supporting role ", and this supporting role is helpful for EOP release-controlled film intensity, and this also means and has reduced the requirement of release-controlled film thickness and reduce production cost.
Our research is also found; Dextrin be among the present invention VENLAFAXINE HCL EOP as the better selection of filler; Because exerting an influence to institutes such as the rate of dissolution of above-mentioned pump chamber component, osmotic pressuries, dextrin almost is difficult to discover; Therefore can adjust label size and total amount easily with dextrin, realize production operation and control.Simultaneously, the dextrin of certain consumption can form certain " buffering " regulating action for dissolving and osmotic pressure generation structure in the pump chamber.
To sum up; The present invention provides a kind of EOP structure osmotic pump preparation of VENLAFAXINE HCL; Its label is made up of VENLAFAXINE HCL, polyethylene glycol oxide, microcrystalline Cellulose, sodium chloride, dextrin and suitable amount of adhesive (polyvidone) and lubricant (magnesium stearate), to account for the percentage ratio of label weight:
VENLAFAXINE HCL 40%～60%
Sodium chloride 5%～15%
Dextrin 5%～30%
Binding agent is an amount of
Lubricant is an amount of
The preferred polyvidone of binding agent among the present invention, for improving the drug loading amount, it accounts for the label gross weight can be lower than 5%.
The preferred magnesium stearate of lubricant among the present invention, it accounts for the label gross weight can be lower than 0.5%.
Polyethylene glycol oxide should be selected the macromole magnitude among the present invention, selects 5,000,000 usually, and the polyethylene glycol oxide molecular weight of selecting is big more, and its consumption can be low more.
According to the preparation specification requirement, the present invention can allocate according to above-mentioned prescription, to obtain the suitable label of size.When the needs preparation contains venlafaxine 75mg specification (hydrochloric approximately venlafaxine 85mg); The polyethylene glycol oxide usage ratio can correspondingly be dwindled; The microcrystalline Cellulose ratio suitably increases, and carries out the adjusting of label gross weight with dextrin as filler, to obtain to be convenient to the label of suitability for industrialized production; When the needs preparation contains venlafaxine 150mg specification (hydrochloric approximately venlafaxine 170mg); The polyethylene glycol oxide usage ratio can correspondingly increase; Microcrystalline Cellulose and dextrin consumption then reduce, and can obtain the label of high drug loading amount, thereby make the label size be unlikely to excessive.
Following preferred medicine label proportioning can further embody allotment principle of the present invention.
For the preparation specification is the VENLAFAXINE HCL controlled release preparation of 75mg (in venlafaxine), and the weight proportion that preferred label is formed is: 85 parts of VENLAFAXINE HCLs, 5 parts of polyethylene glycol oxides (molecular weight 5,000,000); 40 parts of microcrystalline Cellulose, 10 parts of sodium chloride, 20 parts of dextrin; 5 parts of polyvidones; 0.5 part magnesium stearate is processed the label of the heavily about 165.5mg of sheet, can be pressed into the label that diameter is about 7.0mm～7.5mm after the granulation.
Another preferred label of the preparation of 75mg specification is formed weight proportion and is: 85 parts of VENLAFAXINE HCLs, 5 parts of polyethylene glycol oxides (molecular weight 5,000,000), 40 parts of microcrystalline Cellulose; 15 parts of sodium chloride; 54 parts of dextrin, 10 parts of polyvidones, 1 part of magnesium stearate; Process the label of the heavily about 205mg of sheet, can be pressed into the label that diameter is about 7.5mm～8mm after the granulation.
For the preparation specification is the VENLAFAXINE HCL controlled release preparation of 150mg (in venlafaxine), and the weight proportion that preferred label is formed is: 170 parts of VENLAFAXINE HCLs, 20 parts of polyethylene glycol oxides (molecular weight 5,000,000); 60 parts of microcrystalline Cellulose, 20 parts of sodium chloride, 19 parts of dextrin; 10 parts of polyvidones; 1 part of magnesium stearate is processed the label of the heavily about 300mg of sheet, can be pressed into the label that diameter is about 8.5mm～9mm after the granulation.
Based on the present invention, even the preparation of hydrochloric venlafaxine 170mg, because of principal agent and ratio of adjuvant reach 170: 130; The osmotic pump preparation label size of the EOP structure that obtains also is not more than 9mm; Make things convenient for the patient to take, met clinical demand, and greatly reduced production cost.
VENLAFAXINE HCL EOP preparation of the present invention can adopt this area conventional tablet and art for coating to prepare, wherein, and preferred following method:
After VENLAFAXINE HCL, polyethylene glycol oxide, sodium chloride, microcrystalline Cellulose, polyvidone, dextrin etc. are pulverized respectively; Sieve, mix homogeneously uses ethanol to be wetting agent system soft material; 20 mesh is granulated; Wet grain drying, 18 mesh sieve granulate, add the magnesium stearate lubricant mixing after tabletting promptly get label.
With coating dissolution with solvents semipermeable membrane clothing material and plasticizer or/and porogen makes the semipermeable membrane coating solution.Adopt efficient or fluidized bed coating equipment carries out coating to label, volatilize the coating solvent in the coated tablet; Open the aperture of 1 to 2 diameter between 0.3mm～0.8mm with laser boring at coated tablet; Select the film-coat material of commercially available routine to wrap the layer protecting film clothing again, so that its protection against the tide, attractive in appearance promptly gets VENLAFAXINE HCL EOP preparation.
Insoluble semipermeable membrane clothing comprises semipermeable membrane clothing material and plasticizer or/and porogen, and wherein semipermeable membrane clothing material is selected from cellulose acetate or ethyl cellulose; Plasticizer is selected from one or more in dimethyl phthalate, diethyl phthalate, dibutyl phthalate and the Polyethylene Glycol; Porogen is selected from Polyethylene Glycol-1500, Polyethylene Glycol-4000, one or more in Polyethylene Glycol-6000, sucrose and the polyvinylpyrrolidone; The coating solution solid content of preparation in bulking value percent generally 3%～6%, and coating weightening finish can be controlled in controlled release tablet heavy 3%～8%.Described " coating weightening finish ", available Δ m representes, means behind the coating difference of the weight of label and the ratio of label weight before the release-controlled film garment piece and coating, promptly
In release-controlled film coating operation of the present invention, the coating solvent can adopt this area coating solvent that is suitable for controlled release tablet of the present invention commonly used, one or more in the preferred acetone of the present invention, isopropyl alcohol and the chloroform; Further preferred acetone and the combination of isopropyl alcohol or the combination of acetone and chloroform.
Particularly, the release-controlled film clothing optional but to be not limited to the composition proportioning that the present invention uses following:
Cellulose acetate 100g
Dimethyl phthalate 1g
Polyethylene glycol 1500 20g
Acetone 2500ml
As is known to the person skilled in the art, can adjust rate of drug release within the specific limits easily with coating weightening finish (release-controlled film thickness) and release-controlled film clothing porogen consumption.
Compare with the slow releasing preparation of routine; VENLAFAXINE HCL controlled release tablet of the present invention makes drug release not receive the interference of factors such as gastrointestinal tract environment, wriggling, gastric emptying and influences, and makes blood drug level more steady, has eliminated peak valley phenomenon; Effectively reduce side effect; Reduce administration number of times, improved patient's compliance, satisfied the clinical application needs.
The preparation process of osmotic pump controlled release tablet of the present invention is conventional tabletting, packaging technique, and except that needs laser boring, other process does not have different with conventional preparation.And laser boring has obtained sophisticated production application in this area, and is reliable, and use cost is cheap, and can obtain reliable quality control.Compare with the preparation that do not punch, the present invention need not higher coating weightening finish, can obviously reduce the coating consumptive material and save man-hour, can't produce many potential problems that the perforated membrane osmotic pump preparation brings because of release-controlled film deformation.
Importantly; Compared with present technology; The present invention can obtain the drug loading amount and surpass 50% EOP label; And under this high drug loading amount situation, still can make preparation keep continual and steady release, and this is even more important for big specification VENLAFAXINE HCL durative action preparation: the one, avoided the oversize patient's of causing of tablet dysphagia, and the 2nd, greatly reduce manufacturing cost; The 3rd, reducing the tablet size has and is suitable for the holdup time difference of osmotic pump tablet in gastrointestinal tract when reducing the patient and taking, this means will reduce individual in and the drug effect difference between individuality.
Description of drawings
The cumulative release curve of preparation VENLAFAXINE HCL of the present invention among Fig. 1, the embodiment 1 to 4;
The cumulative release curve of preparation VENLAFAXINE HCL of the present invention among Fig. 2, the embodiment 5 and 6;
The cumulative release curve of Fig. 3, embodiment 2 VENLAFAXINE HCL under two kinds of coating weightening finishes;
The cumulative release curve of Fig. 4, embodiment 5 VENLAFAXINE HCL under two kinds of coating weightening finishes
Fig. 5, embodiment 3 be the cumulative release curve in water, pH=1.2,4.0,6.8 buffer solution
Fig. 6, embodiment 3 are the cumulative release curve of 50rpm, 100rpm, 150rpm at rotating speed
The specific embodiment
To combine specific embodiment and relevant drawings below, the present invention will be carried out detailed explanation, still, below the embodiment that provided just for the present invention is described, be not limitation of the present invention.
Embodiment 1
(1) label prescription
Composition g/1000 sheet
VENLAFAXINE HCL 85
Polyethylene glycol oxide (molecular weight 5,000,000) 5
Polyvidone 5
Magnesium stearate 0.5
Every label theoretical weight: 165.5mg
(2) method for preparing
VENLAFAXINE HCL, polyoxyethylene, microcrystalline Cellulose, sodium chloride, dextrin, polyvidone mix homogeneously with proportioning add ethanol and make soft material in right amount, and 30 mesh sieves are granulated, and 40 ℃ dry down, 20 order granulate.Add the magnesium stearate of proportional quantity, mixing with the shallow concave punch tabletting, promptly gets.
The composition proportioning of release-controlled film clothing is following:
Cellulose acetate 100g
Dimethyl phthalate 1g
Polyethylene glycol 1500 20g
Acetone 2500ml
Get cellulose acetate, polyethylene glycol 1500 and an amount of dimethyl phthalate, add acetone and process coating solution, the coating solid content of preparation is about 5% (w/v); With the label that has prepared in laboratory with small high-efficiency coating machine in above-mentioned coating solution coating to preset coating weightening finish, promptly get the release-controlled film garment piece.
The release-controlled film garment piece with the laser-beam drilling machine punching, and with commercially available premix thin film coating material, carries out the protecting film coating according to the specification requirement of this coating material to punched sheet after intensive drying, promptly get the VENLAFAXINE HCL controlled release tablet.
It is the shallow arc stamping of
that embodiment 1 selects diameter, and the weightening finish of release-controlled film coating is controlled at about 4% scope; Adopt single face laser boring, aperture size is controlled at about about 0.5mm.
(1) label prescription
Composition g/1000 sheet
VENLAFAXINE HCL 85
Polyethylene glycol oxide (molecular weight 5,000,000) 10
Dextrin 25
Polyvidone 5
Magnesium stearate 0.5
Every label theoretical weight: 155.5mg
(2) method for preparing is with embodiment 1.
It is the shallow arc stamping of
that embodiment 2 selects diameter, and the weightening finish of release-controlled film coating is controlled at about 5% scope; Adopt two-sided laser boring, aperture size is controlled at about 0.3mm～0.4mm scope.
Embodiment 3
(1) label prescription
Composition g/1000 sheet
VENLAFAXINE HCL 85
Polyethylene glycol oxide (molecular weight 5,000,000) 5
Microcrystalline Cellulose 35
Sodium chloride 15
Dextrin 54
Magnesium stearate 1
Every label theoretical weight: 205mg
(2) method for preparing is with embodiment 1
It is the shallow arc stamping of
that embodiment 3 selects diameter, and the weightening finish of release-controlled film coating is controlled at about 4% scope; Adopt single face laser boring, aperture size is controlled at about about 0.5mm.
(1) label prescription
Composition g/1000 sheet
VENLAFAXINE HCL 85
Polyethylene glycol oxide (molecular weight 5,000,000) 5
Sodium chloride 15
Dextrin 34
Magnesium stearate 1
Every label theoretical weight: 170mg
(2) method for preparing is with embodiment 1
It is the shallow arc stamping of
that embodiment 4 selects diameter, and the weightening finish of release-controlled film coating is controlled at about 4% scope; Adopt single face laser boring, aperture size is controlled at about about 0.5mm.
Embodiment 5
(1) label prescription
Composition g/1000 sheet
VENLAFAXINE HCL 170
Polyethylene glycol oxide (molecular weight 5,000,000) 20
Dextrin 19
Magnesium stearate 1
Every label theoretical weight: 300mg
(2) method for preparing is with embodiment 1
It is the shallow arc stamping of
that embodiment 5 selects diameter, and the weightening finish of release-controlled film coating is controlled at about 4% scope; Adopt single face laser boring, aperture size is controlled at about about 0.5mm.
(1) label prescription
Composition g/1000 sheet
VENLAFAXINE HCL 170
Polyethylene glycol oxide (molecular weight 5,000,000) 25
Microcrystalline Cellulose 35
Sodium chloride 25
Magnesium stearate 1
Every label theoretical weight: 290mg
(2) method for preparing is with embodiment 1
It is the shallow arc stamping of
that embodiment 6 selects diameter, and the weightening finish of release-controlled film coating is controlled at about 5% scope; Adopt two-sided laser boring, aperture size is controlled at about about 0.3mm～0.4mm.
Embodiment 7
Label prescription and method for preparing are all with embodiment 3, and the weightening finish of the coating of release-controlled film is controlled at about 7%.
Label composition and method for preparing are all with embodiment 6, and the weightening finish of the coating of release-controlled film is controlled at about 7%.
The determination experiment of experimental example 1 different embodiment VENLAFAXINE HCL controlled release tablet release degree
1, sample
VENLAFAXINE HCL controlled release tablet of the present invention is according to the embodiment of the invention 1～8 preparation.
2, experimental technique
Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2005 (dissolution determination first subtraction unit mensuration).With water 900ml is solvent, and rotating speed is that per minute 100 changes, operation in accordance with the law.In the time of 2,4,8,12 and 20 hours, in stripping rotor, get solution 8ml respectively, and in stripping rotor, replenish with volume warm in advance immediately to synthermal water; Get subsequent filtrate,, measure trap in the wavelength of 274nm according to spectrophotography (2005 editions two appendix IV A of Chinese Pharmacopoeia); It is an amount of that precision takes by weighing the VENLAFAXINE HCL reference substance in addition, adds water and make dissolving in right amount and quantitatively be diluted to the solution that contains venlafaxine 70 μ g among every 1ml approximately, measures with method.
3, experimental result
Can know referring to Fig. 1; Mutual allotment principle according to polyethylene glycol oxide of the present invention, microcrystalline Cellulose, sodium chloride and the several components of dextrin; Embodiment 1 to 4 all can obtain close medicine sustained release; Each embodiment chien shih rate of release changes, and prompting is adopted the present invention to design release rate of drugs is further finely tuned, to obtain more to meet the medicine sustained release of clinical requirement.The result of Fig. 2 has supported above-mentioned conclusion equally.
Fig. 3 has shown with different release-controlled film thickness with Fig. 4 result also can regulate release rate of drugs of the present invention easily.
The drug release determination of experimental example 2 preparations of the present invention under different pH medium
1, sample
The embodiment of the invention 3.
2, experimental technique
Discharge not affected by environment for further specifying this osmotic pump preparation to controlled delivery of pharmaceutical agents; Adopt experimental example 1 drug release determination method, respectively with the PBS of reference fluid (purified water), pH=1.2 hydrochloric acid solution, pH=4.5 acetate buffer solution and pH=6.8 as the dissolution release medium.
3, experimental result
Experimental result is shown in release profiles among Fig. 5.Preparation of the present invention carries out drug release determination in different medium, rate of release is affected hardly.
The drug release determination of experimental example 3 preparations of the present invention under different stirring conditions
1, sample
The embodiment of the invention 3.
2, experimental technique
Not affected by environment for further specifying this osmotic pump preparation to controlled delivery of pharmaceutical agents release, adopt different stirring conditions that the release degree is measured, investigate the release degree influence of stirring condition to the VENLAFAXINE HCL osmotic pump controlled release tablet.
3, experimental result
Experimental result is shown in release profiles among Fig. 6.Preparation of the present invention carries out drug release determination under different stirring conditions, and rate of release is affected hardly.
Claims (6)
1. the VENLAFAXINE HCL controlled release tablet is characterized in that, comprises the monolayer label, insoluble semipermeable membrane clothing and small delivery aperture, and wherein, label comprises following composition, to account for the percentage ratio of label weight:
The molecular weight of said polyethylene glycol oxide is 200,000 to 8,000,000.
2. controlled release tablet according to claim 1 is characterized in that, the molecular weight of said polyethylene glycol oxide is 5,000,000.
3. controlled release tablet according to claim 1 is characterized in that, said insoluble semipermeable membrane clothing comprises semipermeable membrane clothing material and plasticizer or/and porogen, and wherein semipermeable membrane clothing material is selected from cellulose acetate or ethyl cellulose; Plasticizer is selected from one or more of dimethyl phthalate, diethyl phthalate and dibutyl phthalate, Polyethylene Glycol; Porogen is selected from Polyethylene Glycol-1500, Polyethylene Glycol-4000, one or more in Polyethylene Glycol-6000, the sucrose.
4. controlled release tablet according to claim 3 is characterized in that, the weightening finish of said insoluble semipermeable membrane clothing should be controlled release tablet heavy 3%～8%.
5. controlled release tablet according to claim 1 is characterized in that, said controlled release tablet single face or upper and lower surface respectively have a small delivery aperture, and the aperture is 0.3mm～0.8mm.
6. according to the method for preparing of the said controlled release tablet of the arbitrary claim of 1-5, it is characterized in that, may further comprise the steps:
Behind VENLAFAXINE HCL, polyethylene glycol oxide, sodium chloride, microcrystalline Cellulose, binding agent, dextrin pulverize separately, sieve mix homogeneously; Use ethanol to be wetting agent system soft material, 20 mesh is granulated, wet grain drying; 18 mesh sieve granulate, add the lubricant mixing after tabletting promptly get label;
With coating dissolution with solvents semipermeable membrane clothing material and plasticizer or/and porogen makes the semipermeable membrane coating solution; Adopt efficient or fluidized bed coating equipment carries out coating to label, volatilize the coating solvent in the coated tablet; Open 1 to 2 aperture with laser boring at coated tablet; Select the film-coat material of commercially available routine to wrap the layer protecting film clothing again, so that its protection against the tide, attractive in appearance promptly gets the VENLAFAXINE HCL controlled release tablet.
Wherein, said coating solvent be selected from acetone and/or with the combination of isopropyl alcohol and/or the combination of acetone and chloroform.
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|---|---|---|---|---|
| CN102670553A (en) * | 2011-03-14 | 2012-09-19 | 北京天衡药物研究院 | Venlafaxine hydrochloride osmotic pump controlled release tablet |
| CN102871982B (en) * | 2012-10-16 | 2014-09-10 | 中国科学院上海药物研究所 | Medicine osmotic pump preparation |
| CN105147878A (en) * | 2015-03-17 | 2015-12-16 | 四川紫颐天堂香草科技开发有限公司 | Lavender essential oil composition and preparation method thereof |
| CN104784145B (en) * | 2015-04-30 | 2017-11-21 | 海安苏博机器人科技有限公司 | A kind of venlafaxine sustained-release preparations and preparation method thereof |
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| CN101584674A (en) * | 2008-05-21 | 2009-11-25 | 上海医药科技发展有限公司 | Venlafaxine hydrochloride sustained-release tablet preparation and preparation method thereof |
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| US6569463B2 (en) * | 1999-11-23 | 2003-05-27 | Lipocine, Inc. | Solid carriers for improved delivery of hydrophobic active ingredients in pharmaceutical compositions |
| CN1923184A (en) * | 2006-10-16 | 2007-03-07 | 北京科信必成医药科技发展有限公司 | Multiple apertures releasing osmosis pump and preparation process thereof |
| CN101584674A (en) * | 2008-05-21 | 2009-11-25 | 上海医药科技发展有限公司 | Venlafaxine hydrochloride sustained-release tablet preparation and preparation method thereof |
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| CN101953822A (en) | 2011-01-26 |
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