CN109966259A - A kind of clonidine hydrochloride microporous membrane permeation pump sustained release tablets and preparation method thereof - Google Patents
A kind of clonidine hydrochloride microporous membrane permeation pump sustained release tablets and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of clonidine hydrochloride microporous membrane permeation pump sustained release tablets and preparation method thereof, belongs to technical field of medicine.The clonidine hydrochloride microporous membrane permeation pump sustained release tablets are made of medicated layer label and semi-transparent film coating.There is the clonidine hydrochloride microporous membrane permeation pump sustained release tablets that the present invention is prepared drug release rate not had good controlled-release effect by gastrointestinal tract variable factor such as wriggling, pH, the influence in gastric emptying time etc.；And preparation process is simple, and it is easy to industrialized production, it effectively solves the disadvantage that existing clonidine hydrochloride controlled release tablet, reduces cost, therefore the value with good practical application.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of microporous membrane permeation pump sustained release tablets of clonidine hydrochloride
And preparation method thereof.
Background technique
Disclosing the information of the background technology part, it is only intended to increase understanding of the overall background of the invention, without certainty
It is considered as recognizing or implying in any form that information composition has become existing skill well known to persons skilled in the art
Art.
Clonidine hydrochloride, entitled 2- [(2,6-DCA) -2 the imino group]-imidazolidine hydrochloride of chemistry, is a kind of maincenter
Property alpha-2 adrenoceptor agonists, the main alpha-2 receptor by excited oblongata back side nucleus tractus solitaril postsynaptic membrane inhibits sympathetic mind
Efferent impulse spread through maincenter, expands peripheral blood vessel, also acts on the imidazoline receptor (I1 receptor) of Rostral ventrolateral medulla,
Decline sympathetic tone, peripheral vascular resistance reduces and generates antihypertensive effect, and FDA ratifies Addrenex within 2009
The clonidine hydrochloride sustained release tablets that Pharmaceuticals company develops, for treating hypertension.On the other hand, clonidine hydrochloride
Can by regulate and control norepinephrine function, promote prefrontal cortex restore inhibit control function, thus reach improve attention and
The effect of learning ability obtains U.S. FDA approval for 2010 and increases indication, for treating the attention deficit of Children and teenager
Mostly dynamic obstacle (ADHD).At present clonidine hydrochloride be used clinically for treatment hypertension, migraine, dysmenorrhea and menopause hectic fever,
Attention deficit hyperactivity disorder.
Clonidine hydrochloride, which has listed preparation, oral quick release tablet, slow-release tablet agent, dripping pill, injection and transdermal patch, mesh
The preparation method of preceding clonidine hydrochloride oral slow-releasing preparation has, and patent CN105395518A prepares spansule and alleviates for treating
Muscle cramp and its severe pain of adjoint skeletal muscle, CN101536981 prepare more capsule lipids and realize slow releasing function,
CN105395506A, CN104138362A, CN104352473A use matrix type slow-release material, CN104352447A,
CN102138906A prepares sustained release pellet by using the coating membrane of addition pore-foaming agent.But inventors have found that above-mentioned clonidine hydrochloride
For fixed output quota product and preparation method thereof there are still content in preparation process is uneven, preparation process is complicated, discharges the problems such as incomplete.
Summary of the invention
In view of the above shortcomings of the prior art, the present invention provide a kind of clonidine hydrochloride microporous membrane permeation pump sustained release tablets and its
Preparation method has sustained-release tablets release speed by gastrointestinal tract variable factor such as wriggling, pH, the influence in gastric emptying time etc.
Good controlled-release effect；And preparation process is simple, and it is easy to industrialized production, effectively solve lacking for existing clonidine hydrochloride controlled release tablet
Point reduces cost, therefore the value with good practical application.
The present invention is achieved through the following technical solutions:
The first aspect of the invention provides a kind of clonidine hydrochloride microporous membrane permeation pump sustained release tablets, the clonidine hydrochloride
Determine microporous membrane permeation pump sustained release tablets to be made of medicated layer label and semi-transparent film coating,
Wherein, the medicated layer label is made of following raw material (percentage):
Clonidine hydrochloride 0.1~0.2%
Penetrating agent is 20%~50%
Retarding agent is 10%~20%
Filler is 20%~50%
Lubricant is 0.5%~2%
Further, penetrating agent can be sodium chloride, glucose, sucrose, lactose, magnesium sulfate, magnesium chloride, potassium sulfate, sulfuric acid
Sodium, d- mannitol, urea, Magnesium succinate, any one or combination in tartaric acid, preferably sodium chloride, glucose, sweet dew
Any one or combination of alcohol, lactose；
Retarding agent can be hydroxypropyl methylcellulose or sodium carboxymethylcellulose (CMC-Na), preferably sodium carboxymethylcellulose；
Filler is microcrystalline cellulose (MCC)；
Magnesium stearate lubricant or talcum powder；Preferably magnesium stearate.
The semi-transparent film coating includes filmogen, pore-foaming agent and plasticizer；
Wherein filmogen select ethyl cellulose, pore-foaming agent PEG400, sucrose, polyvinylpyrrolidone (PVP) or
Propylene glycol, plasticizer are diethyl phthalate (DEP).
Specifically, the preparation method of the sustained release tablets includes:
-- preparation medicated layer label；
-- prepare semi-permeable membrane coating solution；
-- semi-permeable membrane coating solution is sprayed into medicated layer label and is coated to obtain the final product.
Compared with prior art, the beneficial effect that the present invention obtains is:
The present invention provides a kind of clonidine hydrochloride microporous membrane permeation pump sustained release tablets and preparation method thereof for the first time, releases sustained release tablets
Medicine speed is not had good controlled-release effect by gastrointestinal tract variable factor such as wriggling, pH, the influence in gastric emptying time etc.；And it makes
Standby simple process, it is easy to industrialized production, it effectively solves the disadvantage that existing clonidine hydrochloride controlled release tablet, reduces cost, therefore have
There is the value of good practical application.
Detailed description of the invention
Fig. 1 changes over time figure for the rate of release that embodiment 1 prepares clonidine hydrochloride microporous membrane permeation pump sustained release tablets；
Fig. 2 changes over time figure for the rate of release that embodiment 2 prepares clonidine hydrochloride microporous membrane permeation pump sustained release tablets；
Fig. 3 changes over time figure for the rate of release that embodiment 3 prepares clonidine hydrochloride microporous membrane permeation pump sustained release tablets；
Fig. 4 changes over time figure for the rate of release that embodiment 4 prepares clonidine hydrochloride microporous membrane permeation pump sustained release tablets；
Fig. 5 changes over time figure for the rate of release that embodiment 5 prepares clonidine hydrochloride microporous membrane permeation pump sustained release tablets；
Fig. 6 changes over time figure for the rate of release that embodiment 6 prepares clonidine hydrochloride microporous membrane permeation pump sustained release tablets.
Specific embodiment
It is noted that described further below be all exemplary, it is intended to provide further instruction to the present invention.Unless another
It indicates, all technical and scientific terms that the present invention uses have logical with general technical staff of the technical field of the invention
The identical meanings understood.
It should be noted that term used herein above is merely to describe specific embodiment, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singular
Also it is intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or their combination.
As previously mentioned, inventors have found that existing clonidine hydrochloride product and preparation method thereof there are still contain in preparation process
Amount is uneven, preparation process complexity, discharges the problems such as incomplete.
In view of this, it is slow to provide a kind of clonidine hydrochloride microporous membrane permeation pump in the specific embodiment of the present invention
Piece is released, osmotic pump tablet is to can be made into Oros piece (capsule) and infiltration plant people's agent using osmotic pressure principle, can be in vivo
Discharge drug and a kind of release-controlled film coated preparation to uniform constant speed.The maximum feature that osmotic pump tablet releases the drug in vivo, except uniform
Constant outer, rate of releasing drug is suitable for system not by gastrointestinal tract variable factor such as wriggling, pH, the influence in gastric emptying time etc.
The drug of standby various solubility is one kind ideal so far in controlled release formulations for oral administration.In addition to drug, osmotic pumps are formed
The material of piece has material, pore-foaming agent, penetration enhancer and the push agent etc. that constitute semi-permeable membrane being coated compared to mechanical punching
Pore-foaming agent is added in film, improves the permeability of film, pore type osmotic pumps can be made, drug solution can be by spongy film
Micropore release, therefore simplify the preparation process of osmotic pumps, decrease the part due to caused by single release hole
The excessively high caused irritation of drug concentration.
The clonidine hydrochloride microporous membrane permeation pump sustained release tablets are made of medicated layer label and semi-transparent film coating,
Wherein, the medicated layer label is made of following raw material (percentage):
Clonidine hydrochloride 0.1~0.2%
Penetrating agent is 20%~50%
Retarding agent is 10%~20%
Filler is 20%~50%
Lubricant is 0.5%~2%
In still another embodiment of the invention, penetrating agent can for sodium chloride, glucose, sucrose, lactose, magnesium sulfate,
Magnesium chloride, potassium sulfate, sodium sulphate, d- mannitol, urea, Magnesium succinate, any one or combination in tartaric acid, preferably chlorine
Change any one of sodium, glucose, mannitol, lactose or combines；Be conducive to the structure of pore type osmotic pumps using above-mentioned penetrating agent
It builds, by the addition of penetrating agent, generates hyperosmosis, to form osmotic pumps effect, push drug substance stable, lasting release；
In still another embodiment of the invention, retarding agent can be hydroxypropyl methylcellulose or sodium carboxymethylcellulose
(CMC-Na), preferably sodium carboxymethylcellulose；Retarding agent plays good sustained drug release effect, by the way that certain mass is added
Sodium carboxymethylcellulose, be conducive to alleviate drug releasing rate, while avoid active pharmaceutical ingredient by gastrointestinal tract variable factor such as
It wriggles, pH, the influence in gastric emptying time etc.；
It should be noted that clonidine hydrochloride itself has certain solubility in water, penetrating agent is added in the present invention
It is easy to cause drug release early period too fast, and the later period easily causes more residual, therefore penetrating agent and resistance of the present invention by screening addition
Stagnant dose, and the amount that optimal control is added reduces release later period medicament residue so that drug releasing rate is stablized；
In still another embodiment of the invention, filler is microcrystalline cellulose (MCC)；Microcrystalline cellulose is as filling
Agent is able to maintain the compactness of label, improves its rate in blocks；
In still another embodiment of the invention, magnesium stearate lubricant or talcum powder；Preferably magnesium stearate.
In still another embodiment of the invention, the semi-transparent film coating includes filmogen, pore-foaming agent and plasticizer；
In still another embodiment of the invention, wherein filmogen select ethyl cellulose, pore-foaming agent PEG400,
Sucrose, polyvinylpyrrolidone (PVP) or propylene glycol, plasticizer are diethyl phthalate (DEP).It is added in coating membrane
Pore-foaming agent, improves the permeability of film, and drug solution can be released by the micropore on spongy film；
In still another embodiment of the invention, the preparation method of the sustained release tablets includes:
-- preparation medicated layer label: clonidine hydrochloride is dissolved in 95% ethyl alcohol or 95% ethyl alcohol PVP solution, is prepared into wetting
The wetting agent of drug containing is added in agent, the sieving of medicine layer auxiliary material, and softwood processed, sieving granulation is dry, and whole grain of being sieved adds lubricant,
It is uniformly mixed, tabletting；
In still another embodiment of the invention, it is 70~90 mesh (preferably 80 mesh) that medicine layer auxiliary material, which crosses grit number,；
Softwood processed, crosses 10~30 meshes (preferably 20 mesh) granulation, and 35~45 DEG C (preferably 40 DEG C) dryings 2~4h (preferably 3h) cross 10
~20 mesh (preferably 18 mesh) sieve whole grain；It is controlled by above-mentioned parameter, is conducive to drug release and stablizes；
-- prepare semi-permeable membrane coating solution: by filmogen, pore-foaming agent and plasticizer with acetone solution to get Coating Solution；
In still another embodiment of the invention, filmogen is ethyl cellulose, the ethyl cellulose quality point
Number is 2.5~3.5% (preferably 3.0%)；By controlling ethyl cellulose mass fraction, semi-permeable membrane coating solution can effectively improve
Pore；
-- semi-permeable membrane coating solution is sprayed into medicated layer label and is coated to obtain the final product.
In still another embodiment of the invention, it is coated in preparation process, controlled at 45 ± 5 DEG C；Be conducive to mention
High coating efficiency reduces the generation of damaged tablet.
Explanation is further explained to the present invention by the following examples, but is not construed as limiting the invention.It should be understood that
These examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Embodiment 1
The preparation of drug containing chip
Clonidine hydrochloride is dissolved in 95% ethanol solution of 5%PVP as drug containing wetting agent, sodium chloride, CMC-Na,
MCC crosses 80 meshes, mixes, and wetting agent softwood is added, and crosses the granulation of 20 meshes, and 40 DEG C of dry 3h cross 18 mesh whole grains, and lubrication is added
Agent magnesium stearate is uniformly mixed, tabletting.
The preparation of semi-permeable membrane coating solution
Ethyl cellulose, PEG400 and diethyl phthalate (DEP) are dissolved in acetone, obtain ethyl cellulose quality
Score 3%, PEG400 mass fraction are the 15% of ethyl cellulose, and diethyl phthalate (DEP) mass fraction is ethyl
3% Coating Solution of cellulose.
The preparation of thin membrane coated tablet: label is set in coating pan, sprays into coating solution, and label weight gain 3% keeps temperature (45
± 5) it is packed after DEG C being coated.
It is measured according to four the first methods of general rule of dissolution rate and drug release determination method " Chinese Pharmacopoeia " version, analogue body digested road
Condition, temperature are controlled at 37 DEG C ± 0.5 DEG C, using the fresh purified water of degassing as dissolution medium, using dilute hydrochloric acid, to clonidine hydrochloride
Determine controlled release granule and carry out drug release rate test, respectively 1,2,3,4,6,8,12,16, sample for 24 hours, according to ultraviolet-visible point
Four general rules of light photometry " Chinese Pharmacopoeia " version measure absorbance, calculate accumulative releasing degree according to standard curve, measure release
It is 90.5%, and maintains the long-acting constant release of 16h, sees attached drawing 1.
Embodiment 2
The preparation of drug containing chip
Clonidine hydrochloride is dissolved in 95% ethanol solution of 5%PVP as drug containing wetting agent, lactose, CMC-Na, MCC
80 meshes are crossed, are mixed, wetting agent softwood is added, cross the granulation of 20 meshes, 40 DEG C of dry 3h cross 18 mesh whole grains, and lubricant is added
Magnesium stearate is uniformly mixed, tabletting.
The preparation of semi-permeable membrane coating solution: being dissolved in acetone for ethyl cellulose, PEG400 and diethyl phthalate (DEP),
Ethyl cellulose mass fraction 3% is obtained, PEG400 mass fraction is the 15% of ethyl cellulose, diethyl phthalate
(DEP) mass fraction is 3% Coating Solution of ethyl cellulose.
The preparation of thin membrane coated tablet: label is set in coating pan, sprays into coating solution, and label weight gain 3% keeps temperature (45
± 5) it is packed after DEG C being coated.It is 81.2% that release, which is surveyed, for 24 hours, sees attached drawing 2.
Embodiment 3
The preparation of drug containing chip
Clonidine hydrochloride is dissolved in 95% ethanol solution of 5%PVP as drug containing wetting agent, sodium chloride, CMC-Na,
MCC crosses 80 meshes, mixes, and wetting agent softwood is added, and crosses the granulation of 20 meshes, and 40 DEG C of dry 3h cross 18 mesh whole grains, and lubrication is added
Agent magnesium stearate is uniformly mixed, tabletting.
The preparation of semi-permeable membrane coating solution: being dissolved in acetone for ethyl cellulose, PEG400 and diethyl phthalate (DEP),
Ethyl cellulose mass fraction 3% is obtained, PEG400 mass fraction is the 15% of ethyl cellulose, diethyl phthalate
(DEP) mass fraction is 3% Coating Solution of ethyl cellulose.
The preparation of thin membrane coated tablet: label is set in coating pan, sprays into coating solution, and label weight gain 3% keeps temperature (45
± 5) it is packed after DEG C being coated.Measuring accumulative releasing degree for 24 hours is 75.2%, sees attached drawing 3.
Embodiment 4
The preparation of drug containing chip
Clonidine hydrochloride is dissolved in 95% ethanol solution of 5%PVP as drug containing wetting agent, sodium chloride, CMC-Na,
MCC crosses 80 meshes, mixes, and wetting agent softwood is added, and crosses the granulation of 20 meshes, and 40 DEG C of dry 3h cross 18 mesh whole grains, and lubrication is added
Agent magnesium stearate is uniformly mixed, tabletting.
The preparation of semi-permeable membrane coating solution: ethyl cellulose, PEG400 are dissolved in acetone, obtain ethyl cellulose mass fraction
3%, PEG400 mass fraction are 15% Coating Solution of ethyl cellulose.
The preparation of thin membrane coated tablet: label is set in coating pan, sprays into coating solution, and label weight gain 3% keeps temperature (45
± 5) it is packed after DEG C being coated.Measuring accumulative releasing degree for 24 hours is 71.3%, sees attached drawing 4.
Embodiment 5
The preparation of drug containing chip
Clonidine hydrochloride is dissolved in 95% ethanol solution of 5%PVP as drug containing wetting agent, sodium chloride, CMC-Na,
MCC crosses 80 meshes, mixes, and wetting agent softwood is added, and crosses the granulation of 20 meshes, and 40 DEG C of dry 3h cross 18 mesh whole grains, and lubrication is added
Agent magnesium stearate is uniformly mixed, tabletting.
The preparation of semi-permeable membrane coating solution: being dissolved in acetone for ethyl cellulose, PEG600 and diethyl phthalate (DEP),
Ethyl cellulose mass fraction 3% is obtained, PEG400 mass fraction is the 15% of ethyl cellulose, diethyl phthalate
(DEP) mass fraction is 3% Coating Solution of ethyl cellulose.
The preparation of thin membrane coated tablet: label is set in coating pan, sprays into coating solution, and label weight gain 4% keeps temperature (45
± 5) it is packed after DEG C being coated.Measuring accumulative releasing degree for 24 hours is 83.3%, sees attached drawing 5.
Embodiment 6
The preparation of drug containing chip
Clonidine hydrochloride is dissolved in 95% ethanol solution of 5%PVP as drug containing wetting agent, sodium chloride, CMC-Na,
MCC crosses 80 meshes, mixes, and wetting agent softwood is added, and crosses the granulation of 20 meshes, and 40 DEG C of dry 3h cross 18 mesh whole grains, and lubrication is added
Agent magnesium stearate is uniformly mixed, tabletting.
The preparation of semi-permeable membrane coating solution: being dissolved in acetone for ethyl cellulose, PEG400 and diethyl phthalate (DEP),
Ethyl cellulose mass fraction 3% is obtained, PEG600 mass fraction is the 15% of ethyl cellulose, diethyl phthalate
(DEP) mass fraction is 3% Coating Solution of ethyl cellulose.
The preparation of thin membrane coated tablet: label is set in coating pan, sprays into coating solution, and label weight gain 3% keeps temperature (45
± 5) it is packed after DEG C being coated.Measuring accumulative releasing degree for 24 hours is 80.5%, sees attached drawing 6.
It should be noted that above example is only used to illustrate the technical scheme of the present invention rather than is limited.Although ginseng
It is described the invention in detail according to given example, but those skilled in the art can be as needed to this hair
Bright technical solution is modified or replaced equivalently, without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. a kind of clonidine hydrochloride microporous membrane permeation pumps sustained release tablets, which is characterized in that the clonidine hydrochloride microporous membrane permeation pump
Sustained release tablets are made of medicated layer label and semi-transparent film coating,
Wherein, the medicated layer label is made of following raw material (percentage):
Clonidine hydrochloride 0.1~0.2%
Penetrating agent is 20%~50%
Retarding agent is 10%~20%
Filler is 20%~50%
Lubricant is 0.5%~2%；
The semi-transparent film coating includes filmogen, pore-foaming agent and plasticizer.
2. a kind of clonidine hydrochloride microporous membrane permeation as described in claim 1 pumps sustained release tablets, which is characterized in that
The penetrating agent can be sodium chloride, glucose, sucrose, lactose, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulphate, d- sweet dew
Alcohol, urea, Magnesium succinate, any one or combination in tartaric acid, preferably sodium chloride, glucose, mannitol, lactose are appointed
It anticipates a kind of or combines.
3. a kind of clonidine hydrochloride microporous membrane permeation as described in claim 1 pumps sustained release tablets, which is characterized in that
The retarding agent can be hydroxypropyl methylcellulose or sodium carboxymethylcellulose, preferably sodium carboxymethylcellulose.
4. a kind of clonidine hydrochloride microporous membrane permeation as described in claim 1 pumps sustained release tablets, which is characterized in that
The filler is microcrystalline cellulose.
5. a kind of clonidine hydrochloride microporous membrane permeation as described in claim 1 pumps sustained release tablets, which is characterized in that
The magnesium stearate lubricant or talcum powder；Preferably magnesium stearate.
6. a kind of clonidine hydrochloride microporous membrane permeation as described in claim 1 pumps sustained release tablets, which is characterized in that
The filmogen selects ethyl cellulose；
The pore-foaming agent is PEG400, sucrose, polyvinylpyrrolidone or propylene glycol；
The plasticizer is diethyl phthalate.
7. the preparation method of any one of the claim 1-6 clonidine hydrochloride microporous membrane permeation pump sustained release tablets, which is characterized in that
Include:
-- preparation medicated layer label: being dissolved in 95% ethyl alcohol or 95% ethyl alcohol PVP solution for clonidine hydrochloride, be prepared into wetting agent,
The wetting agent of drug containing is added in the sieving of medicine layer auxiliary material, and softwood processed, sieving granulation is dry, and whole grain of being sieved adds lubricant, mixes
Uniformly, tabletting；
-- prepare semi-permeable membrane coating solution: by filmogen, pore-foaming agent and plasticizer with acetone solution to get Coating Solution；
-- semi-permeable membrane coating solution is sprayed into medicated layer label and is coated to obtain the final product.
8. preparation method as claimed in claim 7, which is characterized in that medicine layer auxiliary material cross grit number be 70~90 mesh (preferably
For 80 mesh)；Softwood processed crosses 10~30 meshes (preferably 20 mesh) granulation, and 35~45 DEG C (preferably 40 DEG C) dry 2~4h are (preferably
3h), 10~20 mesh (preferably 18 mesh) are crossed and sieves whole grain.
9. preparation method as claimed in claim 7, which is characterized in that filmogen is ethyl cellulose, the ethyl cellulose
Plain mass fraction is 2.5~3.5% (preferably 3.0%).
10. preparation method as claimed in claim 7, which is characterized in that in coating preparation process, controlled at 45 ± 5 DEG C.
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Citations (3)
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| CN103550183A (en) * | 2013-09-05 | 2014-02-05 | 合肥立方制药股份有限公司 | Trimetazidine hydrochloride osmotic pump controlled-release tablet and preparation method thereof |
| CN104706614A (en) * | 2013-12-16 | 2015-06-17 | 四川科瑞德制药有限公司 | Tandospirone micropore osmotic pump preparation |
| CN105919943A (en) * | 2016-04-26 | 2016-09-07 | 青岛正大海尔制药有限公司 | Clonidine hydrochloride controlled-release granule and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550183A (en) * | 2013-09-05 | 2014-02-05 | 合肥立方制药股份有限公司 | Trimetazidine hydrochloride osmotic pump controlled-release tablet and preparation method thereof |
| CN104706614A (en) * | 2013-12-16 | 2015-06-17 | 四川科瑞德制药有限公司 | Tandospirone micropore osmotic pump preparation |
| CN105919943A (en) * | 2016-04-26 | 2016-09-07 | 青岛正大海尔制药有限公司 | Clonidine hydrochloride controlled-release granule and preparation method thereof |
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