CN1650847A - Albuterol time controlling pulse slow release oral preparation and its preparation method - Google Patents

Albuterol time controlling pulse slow release oral preparation and its preparation method Download PDF

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CN1650847A
CN1650847A CN 200410016125 CN200410016125A CN1650847A CN 1650847 A CN1650847 A CN 1650847A CN 200410016125 CN200410016125 CN 200410016125 CN 200410016125 A CN200410016125 A CN 200410016125A CN 1650847 A CN1650847 A CN 1650847A
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albuterol
control pulse
time control
oral preparation
release oral
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CN 200410016125
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CN1259040C (en
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金方
奚泉
闻聪
俞雄
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Shanghai Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
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Abstract

An orally taken salbutamol able to release active components in the sequence: predefined time lag, fast pulse release, and slow release is composed of a slow-release microsphere containing salbutamol, a coated quick release layer, and a coated time-lagging layer.

Description

A kind of albuterol time control pulse sustained-release oral preparation and preparation method thereof
Technical field
The present invention relates to the albuterol oral formulations, relate in particular to albuterol time control pulse sustained-release oral preparation and preparation method thereof.
Background technology
The receptor of asthma morbidity is learned and is pointed out, beta receptor hypofunction during the asthma morbidity, this may with asthmatic patient serum in have β 2The autoantibody of receptor, and therefore cause β in the lung 2Rd descends relevant.Treating asthma clinically uses more to be second filial generation beta receptor agonist, to be first-selected (annual world sales volume surpasses 1,000,000,000 dollars) especially with the albuterol.Along with the development of chronobiology and chronopharmacology in recent years, finder's multiple physical signs and some disease demonstrate the characteristics of rhythmicity, the outbreak of the dyspnea of asthmatic patient be the daytime-change night, be the high-incidence season of asthma morning, thereby the ideal mode of administration of bronchial antispasmodic should be 12 administrations in morning and is maintained to point in early mornings 8.
Albuterol is β 2Selective receptor agonists, oral effective, but the half-life is shorter, is about 4 hours.Existing slow releasing preparation can discharge medicine with constant or substantially constant ground speed in a period of time, such release pattern makes blood drug level stable, can improve curative effect, reduce toxicity, in a lot of therapeutic processes, suit, but, in some process, also expose deficiency along with the development of chronobiology and chronopharmacology in recent years.Discover, people's multiple physical signs and some disease demonstrate the characteristics of rhythmicity, as the dyspnea outbreak of asthmatic patient be the daytime-change night, best administration time is points in mornings 12, if take slow releasing preparation before sleeping then can cause the unnecessary waste of medicine, and easily produce toleration.
For this reason, developmental research is a kind of by taking in the suitable dosage of suitable drug between in due course, and it is that people institute is very expected that promptly a kind of pulsatile administration system comes the outbreak of control disease.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of albuterol time control pulse sustained-release oral preparation, to overcome the above-mentioned defective that prior art exists, satisfy people's needs;
Another technical problem that the present invention need solve is the preparation method that discloses described albuterol time control pulse sustained-release oral preparation, to realize suitability for industrialized production.
Technical conceive of the present invention is such:
The present invention is for reducing dosage, avoid take medicine night, special pH value according to gastrointestinal motility regularity and different parts, but require in the preparation principal agent time lag 4~5 hours after taking, therapeutic dose of pulse release, and about 6~7 hours of lasting slow release.Therefore, preparation of the present invention is made up of two parts, i.e. segment pulse and slow-released part.For reducing gastrointestinal factors as far as possible to the influence that drug release absorbs, reduce individual variation, this research design the particle type controlled release system, i.e. rapid release and sustained-release micro-spheres that preparation has good compressibility, bag time lag enteric coating behind the tabletting.
The inventor thinks, use the pulsatile administration preparation of a kind of " controlling by time variable " can be after the period in specified one section time lag, a pulsed release fast is provided on preset time point, and obviously, it is more favourable that this medicine-releasing system seems when treatment has the disease of rhythmicity.But the disease such as the asthma that much have rhythmicity; be not only to be a temporary outbreak 12 of mornings; its symptom usually can last till point in early mornings 8; if the half-life of medicine is shorter; then simple pulsed release just can not be kept effective blood drug concentration to early morning, and two medicine-releasing systems of pulse slow-releasing have just solved this contradiction preferably.The two medicine-releasing systems of pulse slow-releasing can lag behind when specified a pulsed release fast is provided, and continue then slowly to discharge medicine in a period of time, and can reach cooperation disease rhythmicity and treat, and in the effect of a period of time inner control symptom.Such treatment will have maximum patient dependence and minimum side effect, also have the pharmacoeconomics meaning.
Albuterol time control pulse sustained-release oral preparation of the present invention by the slow-releasing microsphere that contains principal agent, contain the immediate release section of principal agent and be wrapped in the slow-releasing microsphere and retardance clothing layer that immediate release section is outer constitutes, wherein:
(1) component of sustained-release micro-spheres and weight percent content comprise:
Principal agent 3~30%
Alcohol dissolubility blocker 60~90%
Plasticizer 4~20%
Dispersant 0~3%.
Said principal agent comprises albuterol and its esters, preferably sulfuric acid albuterol and hydrochloric acid albuterol.
The pure dissolubility blocker of being addressed comprise acrylic resin (RS, NE), in ethyl cellulose or polyvinyl acetate etc. one or more;
The main effect of plasticizer is the vitrification point that reduces the retardance material, and increase its toughness, comprise a kind of or its mixture in triethyl citrate, tributyl citrate, glycerol triacetate, tributyl 2-acetylcitrate, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglycerides, hypromellose or the Polyethylene Glycol;
The dispersant of being addressed comprises one or more in magnesium stearate, micropowder silica gel or the microcrystalline Cellulose;
(2) immediate release section of being addressed comprises the principal agent of pulsed dosage and pharmaceutically acceptable adjuvant, said adjuvant comprises binding agent, filler, surfactant, in dilatancy excipient or the lubricant etc. one or more, said binding agent comprises polyvinylpyrrolidone, a kind of or its mixture in hypromellose or the hydroxypropyl cellulose, said filler comprises amylum pregelatinisatum, a kind of or its mixture of dextrin or Icing Sugar, said surfactant comprises sodium lauryl sulphate, a kind of or its mixture in tween or the poloxamer, the dilatancy excipient specifically comprises microcrystalline Cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium or substitution value are a kind of or its mixture in 5%~16% the hydroxypropyl cellulose; Said lubricant comprises Pulvis Talci, one or more in magnesium stearate or the micropowder silica gel.
Preferred principal agent weight content in the immediate release section is 0.01%~99.9%; The weight ratio of preferred principal agent and adjuvant is 1: 1~3, and the weight ratio of the principal agent in the immediate release section in principal agent and the microsphere is 1: 1~3.
It is outer or the method that slow-releasing microsphere and immediate release section prepare fast disintegrating tablet routinely prepared label that immediate release section can be wrapped in the slow-releasing microsphere.
According to the present invention, preferably adopt the adjuvant of the mixture of dilatancy excipient, surfactant and binding agent as capsule, wherein: weight percent content comprises:
Dilatancy excipient 44%~94%
Surfactant 0~31%
Binding agent 6%~31%
According to the present invention, preferably adopt dilatancy excipient and lubricant adjuvant as tablet.
(3) component of block layer and weight percent content comprise:
Insoluble and the low permeability material 0~80% of water
Water-soluble, height oozes or enteric material 5~90%
Plasticizer 4~15%
Lubricant 3~8%
Insoluble and the low permeability material of water, comprise acrylic resin (RS, NE), a kind of or its mixture in ethyl cellulose or polyvinyl acetate etc.;
In block layer, also contain non-retardance material, comprise water-soluble material, enteric solubility material and high osmosis material, water-soluble material comprises a kind of or its mixture in Polyethylene Glycol and hypromellose or the like, and enteric material comprises a kind of or its mixture in acrylic resin (L), hydroxypropylmethyl cellulose phthalate (HPMCP) and the cellulose acetate phthalate etc.; The high osmosis material comprises acrylic resin (RL).
Be mixed with in the insoluble and low permeability material of water water-soluble, height oozes or enteric material, when controlling the infiltration of moisture with release-controlled film, the consumption of the two is the key of control time lag length, the weightening finish of time lag clothing layer is in the scope of Release Performance repeatability reasonable 8%~12%, the two ratio is generally 40~10: 1, and coating increase heavy influence time lag length.If select for use water-soluble or the hypertonicity material, then should coat enteric film coat at outermost layer.
When only being block layer with water-soluble or/and enteric solubility material, its weightening finish is the key of control time lag length, and the scope of preferred weightening finish is 5%~30%, if select for use water-soluble or the hypertonicity material, then should coat enteric film coat at outermost layer.
The main effect of plasticizer is the film-forming temperature that reduces coating material, and the toughness of increase clothing film, make it to be difficult for be full of cracks, comprise a kind of or its mixture in triethyl citrate, tributyl citrate, glycerol triacetate, tributyl 2-acetylcitrate, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglycerides, hypromellose or the Polyethylene Glycol;
The main effect of lubricant is the viscosity that reduces coating solution, guarantees carrying out smoothly of coating process, comprises Pulvis Talci.
" pharmaceutical polymers is learned, in August, 2000 front page " that the title of the adjuvant that the present invention is used, specification and relevant nature see that Chinese Medicine science and technology publishing house publishes for details.
(4) according to the present invention, between said sustained-release micro-spheres, immediate release section and time lag clothing layer, also be provided with sealing coat, the sealing coat of being addressed comprises water miscible coating material, comprise hypromellose and plasticizer thereof, it act as avoids medicine directly to contact with outer controlled-release material, increases medicine stability.Weightening finish should be 1~4%, and preferred weightening finish is 2%.
The said preparation of the present invention comprises capsule and tablet, and the product that forms in the time of outside immediate release section is wrapped in the slow-releasing microsphere is a capsule; When with the blending of slow-releasing microsphere in immediate release section and the product that forms of tabletting be tablet;
The preparation method of albuterol time control pulse sustained-release oral preparation of the present invention comprises the steps:
(1) pure dissolubility blocker is dissolved in the good solvent, with the principal agent suspendible of particle diameter 10~100um wherein, under condition of stirring, good solvent is added in the poor solvent again, collect the pastille microsphere that forms then.According to principal agent character and preparation requirement, the ratio of ratio, principal agent and the blocker of sphere diameter, good solvent and the poor solvent of particle diameter, the microsphere of control medicine gets final product to such an extent that meet the microsphere that release requires.
The good solvent of being addressed comprise C1~C4 unit alcohol or/and ketone or/and ether, preferred alcohol or acetone.
The poor solvent of being addressed comprises aqueous alkane or/and oils and fats and derivant thereof, preferably paraffin or silicone oil.
Good solvent: poor solvent=1: 3~6, mixing speed are 100~500rpm.
(2) principal agent, adjuvant are adopted conventional method be wrapped in outside the microsphere that step (1) obtained, obtain the medicine carrying ball, adopt method well known in the art then successively at outer wrapping sealing coat, expanding layer and block layer;
Or, contain the adjuvant of expanding material and the microsphere blending that step (1) is obtained with principal agent, and adopt the method compacting of direct compression in blocks, obtain label; Adopt method well known in the art successively at outer wrapping sealing coat and block layer then
(3) according to the method film-making agent or the capsule of routine.
Preparation of the present invention can be used for treatment of asthma and prevention, and the visual patient's age of its dosage, state of an illness decision are generally 0.05~0.2 gram/kg body weight.
Two medicine-releasing systems that the present invention has adopted pulse and slow release to combine.Described dosage form has in the release of one section predetermined time lag afterpulse, and then the characteristic of slow release.Pulse technique is one of key, and the mixture of using enteric solubility resin and hypotonic type resin is to the label coating.After entering intestinal, clothing film midgut soluble resin plays the pore effect at the small intestinal position, and along with the infiltration of moisture, high-expansion adjuvant contained in the medicated core expands gradually, and the clothing film is burst the most at last, realizes that medicine is in blasting type release in morning.
Description of drawings
Fig. 1 be beagal dog ordinary tablet and controlled release lamellar body inner blood concentration ratio.
The specific embodiment
Embodiment 1
(1) sustained-release micro-spheres:
Salbutamol sulfate 10g, acrylic resin RS 22g, acrylic resin RL2g, triethyl citrate 2.4g, magnesium stearate 0.5g, dehydrated alcohol 90ml, liquid paraffin 270ml;
(2) release layer:
Salbutamol sulfate 10g, hypromellose 20g, water 400g;
(4) expanding layer:
Substitution value is 10% hydroxypropyl cellulose 42g, Tween 80 13g, hydroxypropyl cellulose 7g, water 400g;
(3) sealing coat:
Hypromellose 2g, Macrogol 4000 0.5g, water 100g;
(5) block layer:
Ethyl cellulose 11g, acrylic resin L100 1g, tributyl citrate 1g, ethanol 120ml, Pulvis Talci 1g.
An amount of acrylic resin RS and the L100 of dissolving in dehydrated alcohol, add a certain amount of micronized medicine and magnesium stearate, dropwise splash in the liquid Paraffin after being uniformly dispersed and disperse, the following 500 rev/mins of stir abouts of room temperature made the organic solvent volatilization in 6 hours, get the medicine carrying microballoons suspension, behind the elimination foreign minister solution, blot foreign minister's solution of remained on surface with micropowder silica gel, collect microsphere, kept dry.On this microsphere, coat the pulsed dosage medicine.Hypromellose is soluble in water, be made into the solution of 10g/L, the hydroxypropyl cellulose and the sodium lauryl sulphate of adding 10%, stir, it is coated on microsphere surface, coat sealing coat then, at last with ethyl cellulose, acrylic resin L100 is coated on and forms the pulse controlled release layer on the microsphere.Encapsulated behind the mensuration content.
Time (h) ??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9
Release amount (%) ??0 ??0 ??0 ??45.3 ??72.5 ??84.2 ??88.6 ??92.1 ??95.5
Embodiment 2
(1) sustained-release micro-spheres:
Left-handed hydrochloric acid albuterol 3g, ethyl cellulose 80g, Polyethylene Glycol 8g, acetone 90ml, liquid paraffin 270ml;
(2) release layer:
Left-handed hydrochloric acid albuterol 2.5g, polyvinylpyrrolidone 4g, water 80g;
(3) swell layer:
Carboxymethyl starch sodium 12.6g, sodium lauryl sulphate 6g, hypromellose 1.5g, water 150g;
(4) sealing coat:
Hypromellose 2g, dibutyl sebacate 0.4g, water 40g;
(5) block layer:
Acrylic resin L100 30D 45g, dibutyl sebacate 0.5g, Pulvis Talci 1.5g, water 45g
Time (h) ??1 ??2 ??3 ??4 ??5 ??6 ??7
Release amount (%) ??0 ??0 ??0 ??45.5 ??67.5 ??79.5 ??90.2
Technology and roughly the same preceding.The sustained-release micro-spheres preparation technology parameter is a mixing speed: 150 rev/mins, and mixing time: 5 hours
Embodiment 3
(1) sustained-release micro-spheres:
Salbutamol sulfate 8g, ethyl cellulose 24g, Polyethylene Glycol 2.4g, magnesium stearate 0.63g, dehydrated alcohol 180ml, liquid paraffin 550ml;
(2) release layer:
Salbutamol sulfate 4g, polyvinylpyrrolidone 8g, water 150g;
(3) swell layer:
Polyvinylpolypyrrolidone 8g, hypromellose 1g, water 100g;
(4) sealing coat:
Hypromellose 1g, Polyethylene Glycol 0.1g, water 30g;
(5) block layer:
Acrylic resin L100 3g, tributyl citrate 0.3g, Pulvis Talci 0.2g, ethanol 100ml.
Time (h) ??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9
Release amount (%) ??0 ??0 ??0 ??20.3 ??30.5 ??45.6 ??65.5 ??78.6 ??89.2
Technology and roughly the same preceding.The sustained-release micro-spheres preparation technology parameter is a mixing speed: 200 rev/mins, and mixing time: 1 hour
Embodiment 4
(1) sustained-release micro-spheres:
Left-handed hydrochloric acid albuterol 1.4g, acrylic resin RS 24g, Polyethylene Glycol 2.1g, magnesium stearate 0.6g, dehydrated alcohol 200ml, liquid paraffin 600ml;
(2) release layer:
Left-handed hydrochloric acid albuterol 1g, hypromellose 2.5g, water 80g;
(3) swell layer:
Low-substituted hydroxypropyl cellulose 4g, Tween 80 2g, hypromellose 2g, water 200ml
(4); Sealing coat:
Hypromellose 0.8g, Polyethylene Glycol 0.08g, water 28g;
(5) block layer:
Hypromellose 10000cps 12g, triethyl citrate 1.2g, Pulvis Talci 1g, water 400ml.
(6) enteric layer
Cellulose acetate phthalate 6g, triethyl citrate 0.6g, Pulvis Talci 0.8g, ethanol 100ml
Time (h) ??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9
Release amount (%) ??0 ??0 ??0 ??0 ??45.3 ??72.5 ??84.2 ??88.6 ??92.1
Technology and roughly the same preceding, sustained-release micro-spheres preparation technology parameter mixing speed: 450 rev/mins, mixing time: 3 hours.
Embodiment 5
(1) sustained-release micro-spheres:
Left-handed hydrochloric acid albuterol 3g, acrylic resin RS 14g, Polyethylene Glycol 1.4g, microcrystalline Cellulose 0.3g, dehydrated alcohol 90ml, liquid paraffin 350ml;
(2) release layer:
Left-handed hydrochloric acid albuterol 3g, hypromellose 6g, water 200g;
(3) swell layer:
Polyvinylpolypyrrolidone 5g, sodium lauryl sulphate 1.5g, hypromellose 1g, water 100g;
(4) sealing coat:
Hypromellose 0.8g, Polyethylene Glycol 0.1g, water 25g;
(5) block layer:
Acrylic resin RS 30D 15g, hypromellose 1.6g, Glycerine 1,3-diacetate 0.5g, Pulvis Talci 0.4g, water 45g
(6) acrylic resin L100 5g, triethyl citrate 0.5g, Pulvis Talci 0.5g, ethanol 100ml technology is the same, and sustained-release micro-spheres prepares mixing speed: 300 rev/mins, mixing time: 2 hours.
Embodiment 6
(1) sustained-release micro-spheres:
Left-handed hydrochloric acid albuterol 1g, acrylic resin RS 11.5g, acrylic resin RL 1.5g, triethyl citrate 1.5g, magnesium stearate 0.6g, dehydrated alcohol 90ml, liquid paraffin 270ml;
(2) release layer:
Left-handed hydrochloric acid albuterol 0.9g, hypromellose 2g, water 30g;
(3) swell layer:
Substitution value is 12% hydroxypropyl cellulose 4g, Tween 80 0.8g, hypromellose 0.5g, water 50g;
(4) sealing coat:
Hypromellose 0.5g, Polyethylene Glycol 0.05g, water 10g;
(5) block layer:
Ethyl cellulose 4g, acrylic resin L100 0.5g, tributyl citrate 0.5g, ethanol 100ml, Pulvis Talci 0.3g.
Technology is the same, sustained-release micro-spheres preparation technology parameter: mixing speed: 200 rev/mins, and mixing time: 6 hours.
Embodiment 7
Slow-release micro-pill also can with the proper auxiliary materials tabletting, coat the enteric coating film then on sheet surface or contain the retardancy clothing film of enteric pore material, can realize the double mode release of pulse slow-releasing equally.
An amount of acrylic resin RS and the L100 of dissolving in dehydrated alcohol, add the recipe quantity medicine, TEC and magnesium stearate, dropwise splash in the liquid Paraffin after being uniformly dispersed and disperse, the following 600 rev/mins of stir abouts of room temperature volatilized organic solvent in 6 hours fully, got the medicine carrying microballoons suspension, behind the elimination foreign minister solution, blot foreign minister's solution of remained on surface with micropowder silica gel, collect microsphere, kept dry.Adopt the dry method direct compression, the label of compacting 5mg/ sheet.Take by weighing principal agent, sustained-release micro-spheres, microcrystalline Cellulose by recipe quantity, L-HPC, amylum pregelatinisatum, magnesium stearate is with equivalent incremental method mix homogeneously, tabletting.Acrylic resin RS and L100 with recipe quantity is coated on the label with coating pan, gets pulsatile release tablets.
(1) sustained-release micro-spheres:
Salbutamol sulfate 14g, acrylic resin RS 180g, acrylic resin L100 30g, Glycerine 1,3-diacetate 21g, magnesium stearate 6.3g, dehydrated alcohol 1500ml, liquid Paraffin 4500ml;
(2) label:
Salbutamol sulfate 14g, microcrystalline Cellulose KG-801 350g, microcrystalline Cellulose PH-302100g, low-substituted hydroxypropyl cellulose 40g, amylum pregelatinisatum 250g, magnesium stearate 1g;
(3) pulse sheet:
Acrylic resin RS 80g, acrylic resin L100 40g, triethyl citrate 8g, Pulvis Talci 10g, dehydrated alcohol 2000ml.
Time (h) ??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9
Release amount (%) ??0 ??0 ??0 ??50.1 ??65.2 ??78.5 ??88.8 ??91.3 ??95.5
To beagal dog ordinary tablet and controlled release lamellar body inner blood concentration ratio, its result such as Fig. 1.As seen from Figure 1, the preparation that is made by the present invention is compared the release pattern with general dose significant difference, has promptly realized the dual release of slow release after the first pulse.

Claims (19)

1. an albuterol time control pulse sustained-release oral preparation is characterized in that, by the slow-releasing microsphere that contains principal agent, contain the immediate release section of principal agent and be wrapped in the slow-releasing microsphere and retardance clothing layer that immediate release section is outer constitutes.
2. albuterol time control pulse sustained-release oral preparation according to claim 1 is characterized in that, the component and the weight percent content of sustained-release micro-spheres comprise:
Principal agent 3~30%
Alcohol dissolubility blocker 60~90%
Plasticizer 4~20%
Dispersant 0~3%
Said principal agent comprises albuterol and its esters;
The pure dissolubility blocker of being addressed comprise acrylic resin (RS, NE), in ethyl cellulose or the polyvinyl acetate one or more;
The plasticizer of being addressed comprises a kind of or its mixture in triethyl citrate, tributyl citrate, glycerol triacetate, tributyl 2-acetylcitrate, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglycerides, hypromellose or the Polyethylene Glycol;
The dispersant of being addressed comprises one or more in magnesium stearate, micropowder silica gel or the microcrystalline Cellulose.
3. albuterol time control pulse sustained-release oral preparation according to claim 2 is characterized in that, said principal agent is salbutamol sulfate or hydrochloric acid albuterol.
4. albuterol time control pulse sustained-release oral preparation according to claim 1, it is characterized in that, the immediate release section of being addressed comprises the principal agent of pulsed dosage and pharmaceutically acceptable adjuvant, and said adjuvant comprises one or more in binding agent, filler, surfactant, dilatancy excipient or the lubricant.
5. albuterol time control pulse sustained-release oral preparation according to claim 4, it is characterized in that, said binding agent comprises polyvinylpyrrolidone, a kind of or its mixture in hypromellose or the hydroxypropyl cellulose, said filler comprises amylum pregelatinisatum, a kind of or its mixture of dextrin or Icing Sugar, said surfactant comprises sodium lauryl sulphate, a kind of or its mixture in tween or the poloxamer, the dilatancy excipient comprises microcrystalline Cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium or substitution value are a kind of or its mixture in 5%~16% the hydroxypropyl cellulose; Said lubricant comprises Pulvis Talci, one or more in magnesium stearate or the micropowder silica gel.
6. albuterol time control pulse sustained-release oral preparation according to claim 4 is characterized in that the weight ratio of principal agent and adjuvant is 1: 1~3 in the immediate release section, and the weight ratio of the principal agent in the immediate release section in principal agent and the microsphere is 1: 1~3.
7. albuterol time control pulse sustained-release oral preparation according to claim 1 is characterized in that, the component and the weight percent content of block layer comprise:
Insoluble and the low permeability material 0~80% of water
Water-soluble, height oozes or enteric material 5~90%
Plasticizer 4~15%
Lubricant 3~8%.
8. albuterol time control pulse sustained-release oral preparation according to claim 7 is characterized in that, the insoluble and low permeability material of water comprise acrylic resin (RS, NE), a kind of or its mixture in ethyl cellulose or the polyvinyl acetate.
9. albuterol time control pulse sustained-release oral preparation according to claim 7, it is characterized in that, in block layer, also contain non-retardance material, comprise water-soluble material, enteric solubility material and high osmosis material, water-soluble material comprises a kind of or its mixture in Polyethylene Glycol and the hypromellose, and enteric material comprises a kind of or its mixture in acrylic resin (L), hydroxypropylmethyl cellulose phthalate and the cellulose acetate phthalate; The high osmosis material comprises acrylic resin (RL).
10. albuterol time control pulse sustained-release oral preparation according to claim 7, it is characterized in that, be mixed with in the insoluble and low permeability material of water water-soluble, height oozes or enteric material, the weightening finish of time lag clothing layer is in 8%~12% scope, the two ratio is 40~10: 1, select for use water-soluble or during the hypertonicity material outermost layer coat enteric film coat.
11. albuterol time control pulse sustained-release oral preparation according to claim 7, it is characterized in that when being block layer with water-soluble or/and enteric solubility material, its weightening finish scope is 5%~30%, select for use water-soluble or the hypertonicity material, coat enteric film coat at outermost layer.
12. albuterol time control pulse sustained-release oral preparation according to claim 7; it is characterized in that; plasticizer comprises a kind of or its mixture in triethyl citrate, tributyl citrate, glycerol triacetate, tributyl 2-acetylcitrate, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglycerides, hypromellose or the Polyethylene Glycol, and lubricant comprises Pulvis Talci.
13., it is characterized in that also be provided with sealing coat between said sustained-release micro-spheres, immediate release section and the time lag clothing layer, the sealing coat of being addressed comprises water miscible coating material according to each described albuterol time control pulse sustained-release oral preparation of claim 1~12.
14. albuterol time control pulse sustained-release oral preparation according to claim 13 is characterized in that, immediate release section is wrapped in the label of slow-releasing microsphere fast disintegrating tablet outer or that slow-releasing microsphere and immediate release section are prepared into routinely.
15. albuterol time control pulse sustained-release oral preparation according to claim 14 is characterized in that said preparation comprises capsule and tablet.
16. albuterol time control pulse sustained-release oral preparation according to claim 15 is characterized in that, adopts the adjuvant of the mixture of dilatancy excipient, surfactant and binding agent as capsule, weight percent content comprises:
Dilatancy excipient 44%~94%
Surfactant 0~31%
Binding agent 6%~31%.
17. albuterol time control pulse sustained-release oral preparation according to claim 15 is characterized in that, adopts dilatancy excipient and the lubricant adjuvant as tablet.
18. the preparation method according to each described albuterol time control pulse sustained-release oral preparation of claim 1~17 is characterized in that, comprises the steps:
(1) pure dissolubility blocker is dissolved in the good solvent, wherein, under stirring good solvent is added in the poor solvent, collect the pastille microsphere that forms then the principal agent suspendible;
The good solvent of being addressed comprise C1~C4 unit alcohol or/and ketone or/and ether;
The poor solvent of being addressed comprises aqueous alkane or/and oils and fats and derivant thereof;
(2) principal agent, adjuvant are adopted conventional method be wrapped in outside the microsphere that step (1) obtained, obtain the medicine carrying ball, adopt method well known in the art then successively at outer wrapping sealing coat, expanding layer and block layer;
Or, contain the adjuvant of expanding material and the microsphere blending that step (1) is obtained with principal agent, and adopt the method compacting of direct compression in blocks, obtain label; Adopt method well known in the art successively at outer wrapping sealing coat and block layer then;
(3) according to the method film-making agent or the capsule of routine.
19. the preparation method of albuterol time control pulse sustained-release oral preparation according to claim 18 is characterized in that good solvent: poor solvent=1: 3~6, mixing speed are 100~500rpm.
CN 200410016125 2004-02-04 2004-02-04 Albuterol time controlling pulse slow release oral preparation and its preparation method Expired - Fee Related CN1259040C (en)

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Application Number Priority Date Filing Date Title
CN 200410016125 CN1259040C (en) 2004-02-04 2004-02-04 Albuterol time controlling pulse slow release oral preparation and its preparation method

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CN1650847A true CN1650847A (en) 2005-08-10
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102309468A (en) * 2011-09-23 2012-01-11 深圳市嘉轩医药科技发展有限公司 Levalbuterol hydrochloride oral controlled release tablet capsule and preparation method thereof
CN102429892A (en) * 2011-12-06 2012-05-02 江苏大学 Levalbuterol sulfate pulsatile capsule and preparation method thereof
CN104856971A (en) * 2015-05-15 2015-08-26 暨南大学 Pulse double-release preparation as well as preparation method and application thereof
CN114053218A (en) * 2020-08-06 2022-02-18 武汉科福新药有限责任公司 Nadolol sustained-release oral liquid and preparation method thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100581540C (en) * 2006-09-15 2010-01-20 上海医药(集团)有限公司 Isosorbide mononitrate timing quick-release and slow-release preparation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102309468A (en) * 2011-09-23 2012-01-11 深圳市嘉轩医药科技发展有限公司 Levalbuterol hydrochloride oral controlled release tablet capsule and preparation method thereof
CN102429892A (en) * 2011-12-06 2012-05-02 江苏大学 Levalbuterol sulfate pulsatile capsule and preparation method thereof
CN104856971A (en) * 2015-05-15 2015-08-26 暨南大学 Pulse double-release preparation as well as preparation method and application thereof
CN104856971B (en) * 2015-05-15 2019-05-14 暨南大学 A kind of pulse dual-release preparation and the preparation method and application thereof
CN114053218A (en) * 2020-08-06 2022-02-18 武汉科福新药有限责任公司 Nadolol sustained-release oral liquid and preparation method thereof
CN114053218B (en) * 2020-08-06 2022-11-15 武汉科福新药有限责任公司 Nadolol sustained-release oral liquid and preparation method thereof

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