CN106727406A - A kind of controlled release composition containing Doxazosin and preparation method thereof - Google Patents

Abstract

The invention provides a kind of controlled release composition containing Doxazosin, comprising：(a), pastille label；(b), water-insoluble pellicle；(c), hole on water-insoluble pellicle；Wherein, label includes 20~60 weight % medicine-containing particles, 10~30 weight % PEOs, 4~12 weight % HPMCs, 5~10 weight % osmotic pressure regulators, 30~50 weight % fillers and 1~5 weight % lubricants；Semipermeable membrane is made up of 80~90 weight % filmogens, 5~10 weight % plasticizer and 5~10 weight % pore-foaming agents.Controlled release preparation process is simple of the invention, quality controllable, drugloading rate is high, release time extension.

Description

A kind of controlled release composition containing Doxazosin and preparation method thereof

Technical field

The present invention relates to field of medicaments drug preparation technique.More particularly, to a kind of controlled release combination containing Doxazosin Thing and preparation method thereof.

Background technology

Doxazosin (Doxazosin) is a kind of retarding agents of α 1, can cause the lax of blood vessel (including vein and artery) and Expansion, increases CBF, can also make prostate and neck of urinary bladder loosening all muscles, promotes urination.It is high that the medicine is used clinically for treatment Blood pressure and and benign prostatic hyperplasis.Its mesylate, i.e. Carclura are clinically commonly used, chemical name is 1- (4- Amino -6,7- dimethoxy -2- quinazolyls) -4- [(2,3- dioxies-Isosorbide-5-Nitrae-benzo two dislikes -2- bases) carbonyl] piperazine methanesulfonic acid Salt.Carclura is white or off-white color crystalline powder, and odorless is tasteless, its slightly soluble in ethanol, methyl alcohol, in water Middle soluble,very slightly (solubility is about 0.8%, 25 DEG C).Because Carclura is extremely low in solubility, it is difficult to be prepared into one As sustained-release preparation.

Osmotic pump preparation is the controlled release medicine-releasing system being made using permeable pressure head inside and outside pellicle, has obvious zero level to release Medicine feature, its inside and outside drug release correlation is good, and drug release behavior pH value, gastrointestinal peristalsis, the interior food of stomach hardly by dissolution medium Thing etc. influences, therefore has become ideal a kind of controlled release formulations for oral administration in clinical practice.Osmotic pump preparation is initially related to For water soluble drug, because water soluble drug is soluble in water in itself, it can form certain oozing after dissolving in the formulation Pressure, is conducive to the release of medicine thoroughly.But, research shows, the active material obtained by high-flux medicaments sifting there are about 40% is Slightly water-soluble, and insoluble drug can influence its insoluble drug release due to poorly water-soluble, it is difficult to it is applied to clinic, therefore research It is significant with exploitation insoluble drug controlled releasing penetrant pump.

At present, push-pull osmotic pump preparation (PPOP), be also called double layer osmotic pump preparation be realize insoluble drug constant speed, One of ideal form for persistently discharging.Push-pull osmotic pump preparation is made up of medicated layer, boosting layer and pellicle, in water Property environment in outside moisture through semi-permeable membrane enter medicated layer and boosting layer after, make medicated layer aquation formed pastille suspension, and Polymer water uptake expansion in boosting layer, promotes pastille suspension to be disengaged through aperture.For example, Pfizer Inc. production can more China (Cardura XL) is the double-layer osmotic pump controlled-release tablet of Doxazosin, and one layer is medicine layer, by medicine plus some hydrotropies, suspending Agent is constituted；Another layer is boosting layer, mainly by absorbing water after can swelling macromolecule constitute.The infiltration of Pfizer Inc.'s production Although pump preparation realizes the Zero order release of Doxazosin, but its preparation technology is complicated, and production cost is high and technology controlling and process ring Section is more, easily causes quality problems.

In addition, the country has been also carried out various improvement for Doxazosin osmotic pump preparation.Chinese patent application 200710165689.3, by the minds of piece use necessary solubilizer, solubilizer or change Doxazosin into salt type, Or be surfactant, the solubility of Doxazosin is increased, so as to apply for a kind of Doxazosin control of single chamber individual layer Piece preparation method is released, its inventive principle has similar with Chinese patent application 200810103429.8 (a kind of Gliclazide controlled release tablets) Part, but its technique is increasingly complex, it is desirable to punched in the upper and lower surface of tablet, acquired a certain degree of difficulty in industrialization.It is Chinese special Profit application 201110006650.3 prepares Doxazosin single chamber list using suitable polyoxyethylene as osmotic pressure active material The osmotic pump controlled release tablet of layer one side punching, solves the difficulty that Doxazosin is difficult to prepare mono-layer osmotic pump piece as slightly solubility medicine Topic, by relatively simple process realize generally need double-layer osmotic pump tablet can be only achieved controlled-release effect, and with it is current In the market sell can more magnificent (Cardura XL) intra-body data it is similar, but the drugloading rate of said preparation and extension release time It is limited.

The content of the invention

In order to simplify production technology, and improve the drugloading rate of Doxazosin and the release time of extension Doxazosin, this Invention provides a kind of controlled release composition containing Doxazosin and preparation method thereof.The present invention be by following technical scheme come Realize.

On the one hand, the invention provides a kind of controlled release composition containing Doxazosin, it includes following components：

(a), pastille label, wherein described active medicine is Carclura；

(b), water-insoluble pellicle；With

(c), hole on water-insoluble pellicle.

Label of the invention is compressed tablets, has one layer of pellicle of water-insoluble in the Surface coating of label, works as said preparation Into after dissolution medium, the water in medium is rapidly soaked into film and dissolves medicine, and produced Thief zone pressure official post obtains medicine Thing disengages through the hole on pellicle.By multifactor, the final medicine energy such as thickness, osmotic pressure, pore size for controlling coating membrane It is discharged into medium with constant speed.

Therefore, in the label of controlled release composition of the present invention, the gross weight based on label, label includes 20~60 weight % Medicine-containing particle, 10~30 weight % PEOs, 4~12 weight % HPMCs, 5~10 weight % osmotic pressure are adjusted Section agent, 30~50 weight % fillers and 1~5 weight % lubricants.

Because Doxazosin is insoluble drug, dissolving of the medicine in pellicle is had a strong impact on, it is sandy in order to improve Doxazosin and hydrophilic carrier have been made solid dispersions by the solubility of azoles piperazine, the present invention, and both weight ratios are 1:(4 ~10)；Preferably, hydrophilic carrier is poloxamer or polyvinylpyrrolidone.With Chinese patent application The solubility for being increased Doxazosin using solubilizer in 200710165689.3 is compared, and the present invention utilizes solid dispersion technology more The solubility of Doxazosin is improved well, the drugloading rate of Doxazosin in tablet has been brought up to more than 4% from 2%.But, Applicant further found that, after the solubility of Doxazosin is significantly improved, if not being aided with suitable PEO and hydroxypropyl Cellulose, liquid or can be spread out by release hole quickly, not reach the effect of controlled release, or can not in time disengage piece Core, influences the onset time of medicine.On the basis of lot of experiments, PEO preferable particle size of the invention is 75~150 The particle of micron, and the mean molecule quantity of PEO is 800000~3000000；The mean molecule of HPMC Measure is 80000~130000.

In osmotic pumps technology commonly used in the art, it is micro- that the PEO particle size that piece in-core is used is usually 500 Rice or so, from unlike routine techniques, the present invention is by the size controlling of PEO in the range of 75~150 microns. Applicants have unexpectedly found that, when the size controlling of PEO is in the scope, can and HPMC collective effect, Medicine is set to be discharged with the speed of more constant extension.

In addition, described osmotic pressure regulator is selected from one or more in sodium chloride, lactose, glucose；Filler is selected One or more from lactose, microcrystalline cellulose, mannitol；Lubricant is selected from magnesium stearate, talcum powder, cataloid In one or more.

The barrier disengaged as medicine, the importance of semipermeable membrane is self-evident.In order that the toughness of film increases, keeps film Integrality, it usually needs a certain amount of plasticizer is added in pellicle.Additionally, adding a certain amount of cause in filmogen Hole agent, contributes to the infiltration of water, so as to accelerate the dissolving of medicine.Therefore, the water-insoluble pellicle of controlled release composition of the present invention Comprising filmogen, plasticizer and pore-foaming agent.Wherein, filmogen is selected from ethyl cellulose, cellulose acetate, polyvinyl chloride One or more；Plasticizer is selected from the one kind in repefral, dibutyl phthalate, triethyl citrate Or it is various；Pore-foaming agent is selected from one or more in mannitol, polyethylene glycol.It is preferably based on the gross weight of film, semipermeable membrane It is made up of 80~90 weight % filmogens, 5~10 weight % plasticizer and 5~10 weight % pore-foaming agents.

Release hole size is also the key factor of influence influence drug release rate, total in controlled release composition of the invention, Bore dia on water-insoluble pellicle is preferably 0.2~0.8mm.

Second aspect, present invention also offers the preparation method of above-mentioned controlled release composition, it is characterised in that including following step Suddenly：

(1) Carclura and hydrophilic carrier, are weighed in proportion, heating water bath carries hydrophily to 55~65 DEG C Body melts, and is subsequently adding the Carclura dissolved with absolute ethyl alcohol and dichloromethane, and stirring makes solvent volatilize, will be molten Melt thing and pour into tiling on flat board, freezed in -20 DEG C 5~8 hours, be then vacuum dried 24~48 hours, crush 80 mesh sieves, Obtain medicine-containing particle；

(2) PEO, is made to cross 100~200 mesh sieves, HPMC, osmotic pressure regulator, filler and profit Lubrication prescription crosses 60~80 mesh sieves, is first well mixed medicine-containing particle and HPMC, then again with PEO, infiltration Pressure conditioning agent, filler are well mixed, and with ethanol in proper amount aqueous solution softwood, the granulation of 20~40 mesh sieves is dried, whole grain, added Lubricant, compacting obtains label；

(3), by filmogen acetone solution, plasticizer and pore-foaming agent are added, is stirred, obtain coating solution；

(4) label is coated with coating solution, coating weight gain is reached the 6.0~8.0% of label weight, be coated knot Shu Hou, solidifies 20~30 hours at 40~50 DEG C, then using laser or mechanical system tablet a side perforating.

Compared with prior art, the present invention has following advantage：(1) preparation process is simple, it is quality controllable；(2) this hair Bright utilization solid dispersion technology preferably improves the solubility of Doxazosin, makes the drugloading rate of Doxazosin in tablet from 2% Bring up to more than 4%；(3) by controlling the particle size range of PEO, and with HPMC collective effect, make Medicine is discharged with the speed of more constant extension.

Brief description of the drawings

Fig. 1：Hydrochloric acid solution with pH=1.2 as medium, embodiment 1 prepare doxazosin-mesylate controlled-releasing preparation and city The product of selling can be more magnificent contrast cumulative release curve；

Fig. 2：Hydrochloric acid solution with pH=1.2 as medium, embodiment 2 prepare doxazosin-mesylate controlled-releasing preparation and city The product of selling can be more magnificent contrast cumulative release curve；

Fig. 3：Hydrochloric acid solution with pH=1.2 as medium, embodiment 3 prepare doxazosin-mesylate controlled-releasing preparation and city The product of selling can be more magnificent contrast cumulative release curve；

Fig. 4：Hydrochloric acid solution with pH=1.2 as medium, embodiment 4 prepare doxazosin-mesylate controlled-releasing preparation and city The product of selling can be more magnificent contrast cumulative release curve；

Specific embodiment

To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below in conjunction with embodiment to this hair Bright specific embodiment is clearly and completely described.

Embodiment 1：

Pharmaceutical formulation：

Preparation technology：

1st, Carclura and poloxamer are weighed in proportion, heating water bath melts poloxamer to 60 DEG C, so Addition absolute ethyl alcohol and the Carclura of dichloromethane dissolving, stirring, make solvent volatilize afterwards, fused mass are poured into flat Tiled on plate, freezed in -20 DEG C 5 hours, be then vacuum dried 24 hours, crushed 80 mesh sieves, obtain medicine-containing particle；

2nd, PEO is made to cross 200 mesh sieves, HPMC, sodium chloride, lactose and magnesium stearate cross 60 mesh sieves, First medicine-containing particle and HPMC are well mixed, are then well mixed with PEO, sodium chloride, lactose again, With ethanol in proper amount aqueous solution softwood, 40 mesh sieves are pelletized, dry, whole grain, add lubricant, and compacting obtains label；

3rd, by ethyl cellulose acetone solution, repefral and polyethylene glycol 1500 are added, are stirred, Obtain coating solution；

4th, label is coated with coating solution, after coating terminates, is solidified 24 hours at 40 DEG C, then using laser or machine A side perforating of the tool mode in tablet.

Embodiment 2：

Pharmaceutical formulation：

Preparation technology：

1st, Carclura and poloxamer are weighed in proportion, heating water bath melts poloxamer to 55 DEG C, so Addition absolute ethyl alcohol and the Carclura of dichloromethane dissolving, stirring, make solvent volatilize afterwards, fused mass are poured into flat Tiled on plate, freezed in -20 DEG C 6 hours, be then vacuum dried 24 hours, crushed 80 mesh sieves, obtain medicine-containing particle；

2nd, PEO is made to cross 200 mesh sieves, HPMC, lactose, microcrystalline cellulose and magnesium stearate cross 80 , first be well mixed for medicine-containing particle and HPMC by mesh sieve, then again with PEO, lactose, microcrystalline cellulose Well mixed, with ethanol in proper amount aqueous solution softwood, the granulation of 40 mesh sieves is dried, whole grain, adds magnesium stearate, and compacting obtains piece Core；

3rd, by cellulose acetate acetone solution, dibutyl phthalate and mannitol are added, is stirred, wrapped Clothing liquid；

4th, label is coated with coating solution, after coating terminates, is solidified 20 hours at 50 DEG C, then using laser or machine A side perforating of the tool mode in tablet.

Embodiment 3：

Pharmaceutical formulation：

Preparation technology：

1st, Carclura and polyvinylpyrrolidone are weighed in proportion, heating water bath makes polyvinyl pyrrole to 65 DEG C Alkanone melts, and is subsequently adding the Carclura dissolved with absolute ethyl alcohol and dichloromethane, and stirring makes solvent volatilize, will Fused mass is poured on flat board and tiled, and is freezed in -20 DEG C 8 hours, is then vacuum dried 30 hours, crushes 80 mesh sieves, is contained Medicine particle；

2nd, PEO is made to cross 100 mesh sieves, HPMC, glucose, mannitol and talcum powder cross 60 mesh sieves, First medicine-containing particle and HPMC are well mixed, are then mixed with PEO, glucose, mannitol again Even, with ethanol in proper amount aqueous solution softwood, the granulation of 20 mesh sieves is dried, whole grain, adds talcum powder, and compacting obtains label；

3rd, by ethyl cellulose acetone solution, repefral and Macrogol 4000 are added, are stirred, Obtain coating solution；

4th, label is coated with coating solution, after coating terminates, is solidified 24 hours at 45 DEG C, then using laser or machine A side perforating of the tool mode in tablet.

Embodiment 4：

Pharmaceutical formulation：

Preparation technology：

1st, Carclura and polyvinylpyrrolidone are weighed in proportion, heating water bath makes polyvinyl pyrrole to 60 DEG C Alkanone melts, and is subsequently adding the Carclura dissolved with absolute ethyl alcohol and dichloromethane, and stirring makes solvent volatilize, will Fused mass is poured on flat board and tiled, and is freezed in -20 DEG C 6 hours, is then vacuum dried 40 hours, crushes 80 mesh sieves, is contained Medicine particle；

2nd, PEO is made to cross 100 mesh sieves, HPMC, sodium chloride, lactose and cataloid cross 60 , first be well mixed for medicine-containing particle and HPMC by mesh sieve, then mixes with PEO, sodium chloride, lactose again Uniformly, with ethanol in proper amount aqueous solution softwood, the granulation of 20 mesh sieves is dried, whole grain, adds cataloid, and compacting obtains piece Core；

3rd, by polyvinyl-chloride use acetone solution, triethyl citrate and mannitol are added, is stirred, obtain coating solution；

4th, label is coated with coating solution, after coating terminates, is solidified 20 hours at 50 DEG C, then using laser or machine A side perforating of the tool mode in tablet.

Test example 1：Drug release determination

1st, assay method：

Sample is taken, (is surveyed using dissolution rate according to drug release determination method (two the first methods of annex X D of Chinese Pharmacopoeia version in 2010) Determine the device of the method for method second), with hydrochloric acid solution 900ml that pH is 1.2 as solvent, rotating speed is 75 turns per minute, is operated in accordance with the law, Solution 10ml is taken respectively within 1st hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 25 hours, filter Cross, and supplement the hydrochloric acid solution 10ml of 0.1M in process container immediately, take subsequent filtrate as test liquid.Another precision weighs first sulphur Sour Doxazosin reference substance is appropriate, plus the hydrochloric acid solution of 0.1M is configured to 4 μ g/ml solution (using methyl alcohol hydrotropy if necessary), as Reference substance solution.Test sample and reference substance solution are taken, using high performance liquid chromatography (two annex IV of Chinese Pharmacopoeia 2010 edition D) determine, calculate the every burst size of different time.It with octadecylsilane chemically bonded silica is filler that chromatographic condition is, with second Nitrile-water containing 0.5% acetic acid (V/V) and 0.25% triethylamine (V/V) (takes acetic acid 5mL and 2.5mL triethylamine, is diluted with water to 1000mL) (34: 66) are mobile phase, and Detection wavelength is 246nm, as a result as shown in Figure 1 to 4.

2nd, result of the test

Be can be seen that compared with commercially available product " can be more magnificent " by Fig. 1-Fig. 4, release time of the invention is substantially prolonged It is long.

Claims (10)

1. a kind of controlled release composition containing Doxazosin, it is characterised in that comprising following components：

(a), pastille label, wherein described active medicine is Carclura；

(b), water-insoluble pellicle；With

(c), hole on water-insoluble pellicle.

2. controlled release composition as claimed in claim 1, it is characterised in that：Gross weight based on label, label includes 20~60 Weight % medicine-containing particles, 10~30 weight % PEOs, 4~12 weight % HPMCs, 5~10 weight % ooze Conditioning agent, 30~50 weight % fillers and 1~5 weight % lubricants are pressed thoroughly.

3. controlled release composition as claimed in claim 2, it is characterised in that：Medicine-containing particle be by weight ratio be 1:(4~10) The solid dispersion powder that Doxazosin and hydrophilic carrier are made；Preferably, hydrophilic carrier is poloxamer or polyethylene Pyrrolidones.

4. controlled release composition as claimed in claim 2, it is characterised in that：PEO is that particle diameter is 75~150 microns Particle, and the mean molecule quantity of PEO is 800000~3000000.

5. controlled release composition as claimed in claim 2, it is characterised in that：The mean molecule quantity of HPMC is 80000~130000.

6. controlled release composition as claimed in claim 2, it is characterised in that：Described osmotic pressure regulator is selected from sodium chloride, breast One or more in sugar, glucose；Filler is selected from one or more in lactose, microcrystalline cellulose, mannitol；Lubricant Selected from one or more in magnesium stearate, talcum powder, cataloid.

7. controlled release composition as claimed in claim 1, it is characterised in that：Water-insoluble pellicle includes filmogen, plasticising Agent and pore-foaming agent.

8. controlled release composition as claimed in claim 7, it is characterised in that：Filmogen is selected from ethyl cellulose, acetate fiber One or more in element, polyvinyl chloride；Plasticizer is selected from repefral, dibutyl phthalate, citric acid One or more in triethyl；Pore-foaming agent is selected from one or more in mannitol, polyethylene glycol；It is preferably based on film Gross weight, semipermeable membrane is by 80~90 weight % filmogens, 5~10 weight % plasticizer and 5~10 weight % pore-foaming agent groups Into.

9. controlled release composition as claimed in claim 1, it is characterised in that：Bore dia on water-insoluble pellicle is 0.2~0.8mm.

10. the preparation method of a kind of controlled release composition as described in one of claim 1~9, it is characterised in that including following step Suddenly：

(1) Carclura and hydrophilic carrier, are weighed in proportion, heating water bath melts hydrophilic carrier to 55~65 DEG C Change, be subsequently adding the Carclura dissolved with absolute ethyl alcohol and dichloromethane, stirring makes solvent volatilize, by fused mass Pour on flat board and tile, freezed in -20 DEG C 5~8 hours, be then vacuum dried 24~48 hours, crushed 80 mesh sieves, obtain Medicine-containing particle；

(2) PEO, is made to cross 100~200 mesh sieves, HPMC, osmotic pressure regulator, filler and lubricant 60~80 mesh sieves are crossed, first medicine-containing particle and HPMC is well mixed, then adjusted with PEO, osmotic pressure again Section agent, filler are well mixed, and with ethanol in proper amount aqueous solution softwood, the granulation of 20~40 mesh sieves is dried, whole grain, adds lubrication Agent, compacting obtains label；

(3), by filmogen acetone solution, plasticizer and pore-foaming agent are added, is stirred, obtain coating solution；

(4) label is coated with coating solution, coating weight gain is reached the 6.0~8.0% of label weight, after coating terminates, Solidify 20~30 hours at 40~50 DEG C, then using laser or mechanical system tablet a side perforating.