CN106727406B - 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), drug containing label；(b), water-insoluble pellicle；A, hole positioned at water-insoluble pellicle on (c)；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.The controlled release preparation technique of the present invention is simple, quality controllable, and drugloading rate is high, and release time extends.

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 blood vessel (including vein and artery) relaxation and Expansion, increase CBF, can also make prostate and neck of urinary bladder loosening all muscles, promote urination.It is high that the medicine is used clinically for treatment Blood pressure and and benign prostatic hyperplasis.Its mesylate is clinically commonly used, i.e., Carclura, chemical name are 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 for white or off-white color crystalline powder, odorless, tasteless, its slightly soluble in ethanol, methanol, in water Middle soluble,very slightly (solubility be 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 using controlled release medicine-releasing system made of 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 is hardly eaten by the pH value of dissolution medium, gastrointestinal peristalsis, stomach Thing etc. influences, therefore has become a kind of controlled release formulations for oral administration ideal in clinical practice.Osmotic pump preparation initially relates to For water soluble drug, because water soluble drug itself is soluble in water, it can form certain ooze after dissolving in the formulation Pressure thoroughly, is advantageous to the release of medicine.But research shows, there are about 40% by the active material of high-flux medicaments sifting acquisition is Slightly water-soluble, and insoluble drug can influence its insoluble drug release due to poorly water-soluble, it is difficult to applied to clinic, therefore study With developing the significant of insoluble drug controlled releasing penetrant pump.

At present, push-pull osmotic pump preparation (PPOP), also known as double layer osmotic pump preparation be realize insoluble drug constant speed, One of ideal form persistently discharged.Push-pull osmotic pump preparation is made up of medicated layer, boosting layer and pellicle, in water Property environment in outside moisture after semi-permeable membrane enters medicated layer and boosting layer, medicated layer aquation is formed drug containing suspension, and Polymer water uptake expansion in boosting layer, drug containing suspension is promoted to be disengaged through aperture.For example, Pfizer Inc.'s production can be more magnificent (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 forms；Another layer is boosting layer, is mainly made up of the macromolecule that can be swelled after absorbing water.The infiltration of Pfizer Inc.'s production Although pump preparation realizes the Zero order release of Doxazosin, but its preparation technology is complicated, production cost height and technology controlling and process ring Section is more, easily causes quality problems.

In addition, domestic also carried out a variety of improvement for Doxazosin osmotic pump preparation.Chinese patent application 200710165689.3, by using necessary solubilizer in the minds of piece, solubilizer or change Doxazosin into salt type, Or be surfactant, the solubility of Doxazosin is added, 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 punch 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 Doxazosin as slightly solubility medicine and is difficult to prepare the difficulty of mono-layer osmotic pump piece Topic, realized by relatively simple process and usually require the controlled-release effect that can be only achieved of double-layer osmotic pump tablet, and with it is current In the market sell can inside more magnificent (Cardura XL) 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 extend the release time of 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), drug containing label, wherein described active medicine is Carclura；

(b), water-insoluble pellicle；With

(c) a, hole on water-insoluble pellicle.

The label of the present invention is compressed tablets, has the pellicle of one layer 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 caused Thief zone pressure official post obtains medicine Thing disengages through the hole on pellicle.Thickness, osmotic pressure, pore size by controlling coating membrane etc. are multifactor, final medicine energy It is discharged into constant speed in medium.

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 Save agent, 30~50 weight % fillers and 1~5 weight % lubricants.

Because Doxazosin is insoluble drug, dissolving of the medicine in pellicle has been had a strong impact on, it is sandy in order to improve Solid dispersions have been made in Doxazosin and hydrophilic carrier 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 Compared in 200710165689.3 using solubilizer to increase the solubility of Doxazosin, 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 significantly improves, if not being aided with suitable PEO and hydroxypropyl Cellulose, decoction or can be spread out by release hole quickly, not reach the effect of controlled release, or can not disengage piece in time Core, influence 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 as 80000~130000.

In osmotic pumps technology commonly used in the art, the PEO particle size that piece in-core uses is usually 500 micro- Rice or so, 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, energy and HPMC collective effect, Medicine is set to be discharged with the speed of more constant extension.

In addition, one or more of the described osmotic pressure regulator in sodium chloride, lactose, glucose；Filler selects 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 are self-evident.In order that the toughness increase of film, holding film Integrality, it usually needs a certain amount of plasticizer is added in pellicle.In addition, a certain amount of cause is added in filmogen Hole agent, contribute 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 Include filmogen, plasticizer and pore-foaming agent.Wherein, filmogen is in ethyl cellulose, cellulose acetate, polyvinyl chloride One or more；The one kind of plasticizer in repefral, dibutyl phthalate, triethyl citrate It is or a variety of；One or more of the pore-foaming agent 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 an important factor for influence influences drug release rate, total in the controlled release composition of the present 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 then addition absolute ethyl alcohol and the Carclura of dichloromethane dissolving, stirring, make solvent volatilize, will be molten Melt thing and pour on flat board and tile, freezed in -20 DEG C 5~8 hours, be then dried in vacuo 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 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, are dried, whole grain, are added Lubricant, compacting obtain label；

(3), by filmogen acetone solution, plasticizer and pore-foaming agent is added, stirs, obtains coating solution；

(4), label is coated with coating solution, coating weight gain is reached the 6.0~8.0% of label weight, coating 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 technology is simple, quality controllable；(2) this hair The bright solubility that Doxazosin is preferably improved using solid dispersion technology, make 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：Using pH=1.2 hydrochloric acid solution as medium, doxazosin-mesylate controlled-releasing preparation and city prepared by embodiment 1 The product of selling can be more magnificent contrast cumulative release curve；

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

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

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

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 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 afterwards, stirring, make solvent volatilize, fused mass are poured into flat Tiled on plate, freezed in -20 DEG C 5 hours, be then dried in vacuo 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 again with PEO, sodium chloride, lactose, With ethanol in proper amount aqueous solution softwood, the granulation of 40 mesh sieves, dry, whole grain, add lubricant, compacting obtains label；

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

4th, label is coated with coating solution, after coating terminates, 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 afterwards, stirring, make solvent volatilize, fused mass are poured into flat Tiled on plate, freezed in -20 DEG C 6 hours, be then dried in vacuo 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 Mesh sieve, first medicine-containing particle and HPMC are well mixed, then again with PEO, lactose, microcrystalline cellulose It is well mixed, with ethanol in proper amount aqueous solution softwood, the granulation of 40 mesh sieves, dry, whole grain, add magnesium stearate, compacting obtains piece Core；

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

4th, label is coated with coating solution, after coating terminates, 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 then addition absolute ethyl alcohol and the Carclura of dichloromethane dissolving, stirring, make solvent volatilize, will Fused mass is poured on flat board and tiled, and is freezed in -20 DEG C 8 hours, is then dried in vacuo 30 hours, crushed 80 mesh sieves, 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, then mixed with PEO, glucose, mannitol again It is even, with ethanol in proper amount aqueous solution softwood, the granulation of 20 mesh sieves, dry, whole grain, add talcum powder, compacting obtains label；

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

4th, label is coated with coating solution, after coating terminates, 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 then addition absolute ethyl alcohol and the Carclura of dichloromethane dissolving, stirring, make solvent volatilize, will Fused mass is poured on flat board and tiled, and is freezed in -20 DEG C 6 hours, is then dried in vacuo 40 hours, crushed 80 mesh sieves, contained Medicine particle；

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

3rd, by polyvinyl-chloride use acetone solution, triethyl citrate and mannitol is added, stirs, obtains coating solution；

4th, label is coated with coating solution, after coating terminates, 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 according to drug release determination method (two the first methods of annex X D of Chinese Pharmacopoeia version in 2010) using dissolution rate Determine the device of the method for method second), for the hydrochloric acid solution 900ml for being 1.2 using pH 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 0.1M hydrochloric acid solution 10ml in process container immediately, take subsequent filtrate as test liquid.Another precision weighs first sulphur Sour Doxazosin reference substance is appropriate, adds 0.1M hydrochloric acid solution to be configured to 4 μ g/ml solution (if necessary with methanol hydrotropy), 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 burst size of every different time.It with octadecylsilane chemically bonded silica is filler that chromatographic condition, which 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, Detection wavelength 246nm, as a result as shown in Figure 1 to 4.

2nd, result of the test

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

Claims (2)

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

(a), drug containing label, the gross weight based on label, label includes 20~60 weight % medicine-containing particles, 10~30 weight % gather Oxirane, 4~12 weight % HPMCs, 5~10 weight % osmotic pressure regulators, 30~50 weight % fillers With 1~5 weight % lubricants；Wherein, medicine-containing particle be by weight ratio be 1:The Doxazosin and hydrophilic carrier system of (4~10) Into solid dispersion powder, hydrophilic carrier is poloxamer or polyvinylpyrrolidone, and PEO is that particle diameter is 75 ~150 microns of particle, and the mean molecule quantity of PEO is 800000~3000000, HPMC is put down Average molecular weight is 80000~130000；

One or more of the described osmotic pressure regulator in sodium chloride, lactose, glucose；Filler is selected from lactose, micro- One or more in crystalline cellulose, mannitol；The one kind of lubricant in magnesium stearate, talcum powder, cataloid It is or a variety of；

(b), water-insoluble pellicle, the gross weight based on film, semipermeable membrane is by 80~90 weight % filmogens, 5~10 weights % plasticizer and 5~10 weight % pore-foaming agents composition are measured, filmogen is selected from ethyl cellulose, cellulose acetate, polyvinyl chloride In one or more；Plasticizer in repefral, dibutyl phthalate, triethyl citrate one Kind is a variety of；One or more of the pore-foaming agent in mannitol, polyethylene glycol；With

(c) a, hole on water-insoluble pellicle, bore dia are 0.2~0.8mm.

2. a kind of preparation method of controlled release composition as claimed in claim 1, it is characterised in that comprise the following steps：

(1) Carclura and hydrophilic carrier, are weighed in proportion, heating water bath melts hydrophilic carrier to 55~65 DEG C Change, then addition absolute ethyl alcohol and the Carclura of dichloromethane dissolving, stirring, make solvent volatilize, by fused mass Pour on flat board and tile, freezed in -20 DEG C 5~8 hours, be then dried in vacuo 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, are first well mixed medicine-containing particle and HPMC, are then adjusted again with PEO, osmotic pressure Section agent, filler are well mixed, and with ethanol in proper amount aqueous solution softwood, the granulation of 20~40 mesh sieves, are dried, whole grain, are added lubrication Agent, compacting obtain label；

(3), by filmogen acetone solution, plasticizer and pore-foaming agent is added, stirs, obtains 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.