CN102824331A - Zaleplon double-release capsule and preparation method thereof - Google Patents

Zaleplon double-release capsule and preparation method thereof Download PDF

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CN102824331A
CN102824331A CN2012103665328A CN201210366532A CN102824331A CN 102824331 A CN102824331 A CN 102824331A CN 2012103665328 A CN2012103665328 A CN 2012103665328A CN 201210366532 A CN201210366532 A CN 201210366532A CN 102824331 A CN102824331 A CN 102824331A
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micropill
zaleplon
slowbreak
release
hypromellose
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王军
任逢晓
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HENAN ZHONGSHUAI PHARMACEUTICAL SCIENCE DEVELOPMENT Co Ltd
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HENAN ZHONGSHUAI PHARMACEUTICAL SCIENCE DEVELOPMENT Co Ltd
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Abstract

The invention discloses a zaleplon double-release capsule and a preparation method thereof. The zaleplon double-release capsule comprises quick-release pellets and slow-release pellets, wherein each quick-release pellet consists of zaleplon, blank pellet, filler, an adhesive, a disintegrating agent A, an isolation layer film forming material, 0 to 8 percent of a disintegrating agent B and a solubilizer A; and each slow-release pellet comprises zaleplon, blank pellet, filler, an adhesive, the disintegrating agent A, the isolation layer film forming material, the disintegrating agent B, the solubilizer A, a slow-release material, a plasticizer, an antisticking agent and a solubilizer B. The preparation method comprises the following steps: preparing a pellet carrying core; preparing quick-release pellets by the pellet carrying core; preparing slow-release pellets by the quick-release pellets; and filling the quick-release pellets and the slow-release pellets into capsules respectively to obtain the zaleplon double-release capsules. Used for treating insomnia, the zaleplon double-release capsules prepared by the method can increase sleeping period and reduce the number of wakening, so that the treatment effect to a patient can be improved.

Description

Two release capsules of Zaleplon and preparation method thereof
Technical field
The present invention relates to the method for preparing of pharmaceutical field, particularly relate to two release capsule preparations of a kind of Zaleplon and preparation method thereof about pharmaceutical preparation.
Background technology
In early days, central nervous system's medicine barbiturates and Benzodiazepines tranquilizer are used in the treatment of insomnia usually, but it has generally acknowledged side effect, like drowsiness, depressed, addiction etc.Recently, non-benzodiazepine compound, Ambien have been brought into use in the treatment of insomnia TM(zolpidem) and Sonata TM(Zaleplon) is the instance of the medicine of approval.Although available crude drug has been made significant headway, the intrinsic property of this type crude drug such as half-life weak point etc. will influence its effectiveness, side effect situation and patient's acceptance to a great extent.The fast dissolving dosage form of such medicine is normally effective, and the rapid release of medicine soon after fast dissolving dosage form provides and ingested causes sleeping fast; Yet short drug half-life causes the incident of waking up at short sleep time or frequent night, makes patient need take other preparation at night and keeps sleep.
Zaleplon is the sedative hypnotic, chemistry N-[3-(3-cyano pyrazole [1,5-a] pyrimidin-7-yl) phenyl] by name-N-ethyl acetamide.Its molecular formula is: C 17H 15N 5O, molecular weight are 305.34, and structural formula is:
Figure 114216DEST_PATH_IMAGE001
Zaleplon is white or off-white powder; Slightly soluble in ethanol or propylene glycol, almost insoluble in water, the partition coefficient in n-octyl alcohol/water is 1.23.
Zaleplon is the sedative hypnotic, is applicable to the insomnia's of difficulty falling asleep short term therapy, and it brings into play its pharmacological action through acting on gamma aminobutyric acid-Benzodiazepine in the body (GABA-BZ) receptor complex.For the Zaleplon ordinary preparation, Zaleplon is absorbed soon, and peak time is approximately 1 hour, eliminates half-life (t 1/2) being approximately 1 hour, the clinical research result shows that Zaleplon can shorten time for falling asleep, but fails to increase the length of one's sleep and reduce clear-headed number of times.Because Zaleplon has higher fat-soluble and plasma protein binding rate; It is higher that ordinary preparation discharges the too fast blood drug level that makes, and the probability of bringing out side effect (untoward reaction such as symptom such as headache, drowsiness, dizzy, nausea and vomiting, weak, memory difficulty, dreaminess) increases.Therefore, need a kind of new dosage form and specification can improve the problems referred to above.
Summary of the invention
It is two release capsule preparations and preparation method thereof of active component with the Zaleplon that the technical problem that the present invention will solve provides a kind of.Be used for Cure for insomnia through the two release capsule preparations of the Zaleplon of technical scheme of the present invention preparation, can increase the length of one's sleep, reduce clear-headed number of times, thereby improve patient's therapeutic effect.And, produce the two release capsules of Zaleplon through method for preparing of the present invention, can reduce the toxic and side effects of Zaleplon, improve the compliance of medication.
In order to address the above problem, the technical scheme that the present invention adopts is:
The present invention provides a kind of Zaleplon two release capsules, comprises fast release micropill and slowbreak micropill, and the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 20～60% and 80～40%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 5～35%, blank micropill 10～60%, filler 0～30%; Binding agent 1～15%; Disintegrating agent A 0.5～5%, sealing coat filmogen 0～35%, disintegrating agent B 0～8% and solubilizing agent A 0～3%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 5～35%, blank micropill 10～50%; Filler 0～30%, binding agent 1～15%, disintegrating agent A 0.5～5%; Sealing coat filmogen 0～30%, disintegrating agent B 0～8%, solubilizing agent A 0～3%; Slowbreak material 5～30%, plasticizer 0～5%, antiplastering aid 0～10% and solubilizing agent B 0～1%.
According to the two release capsules of above-mentioned Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%, blank micropill 20～50%, filler 5～20%; Binding agent 5～15%; Disintegrating agent A 1～5%, sealing coat filmogen 5～20%, disintegrating agent B 0～7% and solubilizing agent A 0～3%;
Said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%, blank micropill 20～50%, filler 5～20%; Binding agent 5～15%, disintegrating agent A 1～5%, sealing coat filmogen 5～15%; Disintegrating agent B 0～7%, solubilizing agent A 0～3%, slowbreak material 8～25%; Plasticizer 0～3%, antiplastering aid 0～8% and solubilizing agent B 0～1%.
According to the two release capsules of above-mentioned Zaleplon, said blank micropill is any one or more in sucrose micropill, microcrystalline Cellulose micropill, starch micropill, lactose-microcrystalline Cellulose micropill, starch-microcrystalline Cellulose micropill, the sucrose-starch micropill;
Said filler is any one or more in sucrose, lactose, mannitol, starch, microcrystalline Cellulose, Sargassum polysaccharides and the chitosan;
Said binding agent is any one or more in water, dehydrated alcohol, water and ethanol mixing, Opadry, hypromellose, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol and the sodium carboxymethyl cellulose;
Said disintegrating agent A is any one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the carboxymethylcellulose calcium;
Said sealing coat filmogen is any one or more in Opadry, hypromellose, hydroxypropyl cellulose, polyvidone and the polyvinyl alcohol;
Said disintegrating agent B is any one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the carboxymethylcellulose calcium;
Said solubilizing agent A is any one or more in sodium lauryl sulphate, sorbitan fatty acid ester, poloxamer, dodecyl sodium sulfate, Polysorbate, ursodesoxycholic acid, lithium dodecyl sulfate and the Polysorbate;
Said slowbreak material is that ethyl cellulose, hypromellose, polyacrylic resin, polyacrylic resin aqueous dispersion, Aquacoat, hydroxypropyl cellulose, hydroxyethyl-cellulose acetyl cellulose, Lac, cellulose acetate-phthalate ester, cellulose acetate phthalate ester, vinyl acetate phthalate ester, hypromellose phthalate ester, refined gram are suitable, in hypromellose succinate, polylactic acid and the palm wax any one or more;
Said plasticizer is any one or more in triethyl citrate, ATEC, tributyl 2-acetylcitrate, dibutyl sebacate, glyceryl triacetate, Polyethylene Glycol, diethyl phthalate, dibutyl phthalate, tristerin, tributyl citrate, diethyl succinate, fractionated coconut oil and the propylene glycol;
Said antiplastering aid is any one or more in Pulvis Talci, colloidal silica, magnesium stearate, calcium stearate, magnesium silicate and the glyceryl monostearate;
Said solubilizing agent B is any one or more in sodium lauryl sulphate, sorbitan fatty acid ester, poloxamer, dodecyl sodium sulfate, Polysorbate, ursodesoxycholic acid, lithium dodecyl sulfate, Polysorbate, Polyethylene Glycol and the hypromellose.
According to the two release capsules of above-mentioned Zaleplon; It is the sucrose micropill that said fast release micropill supplementary material is formed the empty micropill, and filler is a mannitol, and binding agent is a hypromellose; Disintegrating agent A is a polyvinylpolypyrrolidone; The sealing coat filmogen is hypromellose or Opadry, and disintegrating agent B is a polyvinylpolypyrrolidone, and solubilizing agent A is a sodium lauryl sulphate;
It is the sucrose micropill that said slowbreak micropill supplementary material is formed the empty micropill, and filler is a mannitol, and binding agent is a hypromellose; Disintegrating agent A is a polyvinylpolypyrrolidone; The sealing coat filmogen is hypromellose or Opadry, and disintegrating agent B is a polyvinylpolypyrrolidone, and solubilizing agent A is a sodium lauryl sulphate; The slowbreak material is polyacrylic resin, polyacrylic resin aqueous dispersion or Aquacoat; Plasticizer is Polyethylene Glycol or triethyl citrate, and antiplastering aid is a Pulvis Talci, and solubilizing agent B is Polysorbate or hypromellose.
According to the two release capsules of above-mentioned Zaleplon, the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 20～60% and 80～40%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%, sucrose micropill 20～50%, filler mannitol 5～20%; Binding agent hypromellose 5～15%; Disintegrating agent A polyvinylpolypyrrolidone 1～5%, sealing coat filmogen hypromellose or Opadry 5～20%, disintegrating agent B polyvinylpolypyrrolidone 0～7% and solubilizing agent A sodium lauryl sulphate 0～3%;
With respect to slowbreak part in the two release capsules of Zaleplon; Said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%, sucrose micropill 20～50%, filler mannitol 5～20%; Binding agent hypromellose 5～15%; Disintegrating agent A polyvinylpolypyrrolidone 1～5%, sealing coat filmogen hypromellose or Opadry 5～15%, disintegrating agent B polyvinylpolypyrrolidone 0～7%; Solubilizing agent A sodium lauryl sulphate 0～3%; Slowbreak material polyacrylic resin, polyacrylic resin aqueous dispersion or Aquacoat 8～25%, plasticizer Polyethylene Glycol or triethyl citrate 0～3%, antiplastering aid Pulvis Talci 0～8% and solubilizing agent B Polysorbate or hypromellose 0～1%.
According to the two release capsules of above-mentioned Zaleplon, the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 40% and 60%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 16.1%, sucrose micropill 36.6%, filler mannitol 14.1%; Binding agent hypromellose 8.1%; Disintegrating agent A polyvinylpolypyrrolidone 2.0%, sealing coat filmogen hypromellose 13.9%, disintegrating agent B polyvinylpolypyrrolidone 6.9% and solubilizing agent A sodium lauryl sulphate 2.3%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.3%, sucrose micropill 32.4%; Filler mannitol 12.5%, binding agent hypromellose 7.1%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen hypromellose 12.3%; Disintegrating agent B polyvinylpolypyrrolidone 6.1%, solubilizing agent A sodium lauryl sulphate 2.0%, slowbreak material Aquacoat 11.5%.
The method for preparing of the two release capsules of a kind of above-mentioned Zaleplon; At first pill core is carried in preparation, prepares fast release micropill by carrying pill core, prepares the slowbreak micropill by fast release micropill then; With the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last;
(1), carry the preparation of pill core:
The prescription that carries pill core is Zaleplon 92.4g, sucrose micropill (30-40 order) 210g, filler mannitol 80.85g, binding agent hypromellose 46.2g, disintegrating agent A polyvinylpolypyrrolidone 11.55g, 10% ethanol water 924g;
Preparation process: at first under continuous stirring condition, hypromellose and mannitol joined mass percentage concentration and be in 10% the ethanol water and fully dissolve, be dissolved to clarification; The dissolving back adds raw material Zaleplon and disintegrating agent A polyvinylpolypyrrolidone, continues to stir 1-2h, crosses 40 eye mesh screens, obtains the medicated layer coating solution;
Get 30-40 purpose sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake as the ball core 3* h -1The medicated layer coating solution that obtains is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure is 1.0bar, improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets micropill; The micropill of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2) fast release micropill preparation:
The prescription of fast release micropill is for carrying pill core 400g, sealing coat filmogen hypromellose 72g, disintegrating agent B polyvinylpolypyrrolidone 36g, solubilizing agent A sodium lauryl sulphate 12g, deionized water 1080g;
Preparation process: under constantly stirring,, add disintegrating agent B polyvinylpolypyrrolidone after the dissolving, continue stirring 1h, cross 40 eye mesh screens, get the sealing coat coating solution with being dissolved to clarification in hypromellose and the sodium lauryl sulphate adding deionized water; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 40 ℃, the about 65m of adjustment intake 3* h -1The sealing coat coating solution that obtains is added to aerochamber atomizing coating through end spray mode with the flow velocity of 2ml/min with peristaltic pump; Atomizing pressure is 1.4bar, improves feed flow speed gradually to 6ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3) preparation of slowbreak micropill:
The prescription of slowbreak micropill is fast release micropill 300g, the Aquacoat 156g of 25% solid content, deionized water 156g;
Preparation process: get the Aquacoat of 25% solid content, under continuous stirring, add in the deionized water, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1, the slowbreak layer coating solution of obtaining, use peristaltic pump with end spray mode 1 ml/min pump into aerochamber atomizing coating, atomizing pressure is 1.6bar; Progressively improve feed flow speed to 4ml/min; Intact until the coating solution bag, coating finishes the back and places 50 ℃ of dry 2h in the convection oven, chooses the micropill in the 20-30 eye mesh screen scope; Inspection character and release degree promptly get the slowbreak micropill after qualified;
(4) fill of the two release capsules of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 2: 3 mixed after evenly, promptly get Zaleplon pair release capsules.
According to the two release capsules of above-mentioned Zaleplon, the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 40% and 60%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 19.1%; Sucrose micropill 43.3%, filler mannitol 16.7%, binding agent hypromellose 9.5%; Disintegrating agent A polyvinylpolypyrrolidone 2.4%, sealing coat filmogen Opadry 9.0%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.7%, sucrose micropill 33.3%; Filler mannitol 12.8%, binding agent hypromellose 7.3%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen Opadry 7.0%; Slowbreak material polyacrylic resin 16.3%, plasticizer Polyethylene Glycol 4.9%, antiplastering aid Pulvis Talci 1.6% and solubilizing agent B Polysorbate 0.3%.
The method for preparing of the two release capsules of a kind of above-mentioned Zaleplon; At first pill core is carried in preparation, prepares fast release micropill by carrying pill core, prepares the slowbreak micropill by fast release micropill then; With the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last;
(1), carry the pill core preparation:
Carry the pill core prescription: sucrose micropill (30-40 order) 210g, Zaleplon 92.4g, filler mannitol 80.85g, binding agent hypromellose 46.2g, disintegrating agent A polyvinylpolypyrrolidone 11.55g, 10% ethanol water 924g;
Preparation process: under constantly stirring, in 10% ethanol water, add hypromellose and mannitol, be dissolved to clarification, add Zaleplon and polyvinylpolypyrrolidone after the dissolving, continue to stir 1h, cross 40 eye mesh screens, get the medicated layer coating solution;
Get the sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure 1.0bar improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fine pellet core; The fine pellet core of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2), fast release micropill preparation:
Fast release micropill prescription: carry pill core 400g, Opadry 40g, deionized water 360g;
Preparation process: in deionized water, under stirring, add Opadry, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 45 ℃, the about 80m of intake 3* h -1, gained sealing coat coating solution is added to aerochamber atomizing coating, atomizing pressure 1.8bar with the flow velocity of 1.5ml/min with peristaltic pump earlier through end spray mode, improve feed flow speed gradually to 6ml/min, intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3), slowbreak micropill preparation:
Slowbreak micropill prescription: fast release micropill 250g, the polyacrylic resin aqueous dispersion 176g of 30% solid content, Pulvis Talci 15.8g, Polyethylene Glycol 5.3g, Polysorbate 1.1g, deionized water 211g;
Preparation process: deionized water is added Polyethylene Glycol and Polysorbate under continuous stirring, be dissolved to clarification, slowly add polyacrylic resin aqueous dispersion and Pulvis Talci, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1Get gained slowbreak layer coating solution and pump into aerochamber atomizing coating with peristaltic pump with end spray mode 1.5ml/min, atomizing pressure is 1.4bar, and it is intact to 5ml/min to the coating solution bag progressively to improve feed flow speed; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven; Choose the micropill in the 20-30 eye mesh screen scope, inspection character and release degree promptly get the slowbreak micropill after qualified;
(4), the two release capsule fills of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 2: 3 mixed after evenly, promptly get Zaleplon pair release capsules.
According to the two release capsules of above-mentioned Zaleplon, the effective dose of the Zaleplon in the two release capsules of said Zaleplon is 5～40mg.
The effective dose of the Zaleplon in the two release capsules of the Zaleplon that utilizes technical scheme of the present invention to prepare is 5～40mg, and the effective dose of Zaleplon is preferably 10～30mg.
Positive beneficial effect of the present invention:
1, is used for Cure for insomnia through the two release capsule preparations of the Zaleplon of technical scheme of the present invention preparation, can increases the length of one's sleep, reduce clear-headed number of times, thereby improve patient's therapeutic effect.And, produce the two release capsules of Zaleplon through method for preparing of the present invention, can reduce the toxic and side effects of Zaleplon, improve the compliance of medication.
2, take (the preferred 10-30mg of effective dose) according to the two release capsule effective doses of Zaleplon of the present invention; Whenever take and once can guarantee the interior active drug concentration of body 8 hours lengths of one's sleep the whole night, and can reduce the higher nervus centralis side reaction that causes of blood drug level peak value that ordinary preparation brings; Adopt pharmaceutical formulation of the present invention and method for preparing to produce the two release capsules of Zaleplon simultaneously, can significantly lower differences between batches.
3, the two release capsules of the Zaleplon of the present invention's preparation; The effective dose of Zaleplon is between 5-40mg in two delivery formulations; Be preferably 10-30mg,, have close or identical body giving drugs into nose for dynamic characteristic during different size correspondence different crowd to adapt to different weight crowd's use.
4, the two release capsules of product Zaleplon of the present invention are the dosage regimens with periodic intervals administration instant-free (IR) dosage form, and this dosage causes pulsed blood plasma characteristic usually, have special pharmacological relevant with them and treatment effect.For example, the cleaning phase that PC provided of active component is considered to reduce or prevents the contribution factor of patient to all types of drug resistances between the peak.
5, the two delivery formulations of product Zaleplon of the present invention, it provides the pulsed release profile in vivo, in case administration whereby, wherein immediate release section produces release at short notice, and maximum plasma drug level is provided in 0.1-1.5 hour after administration.After this, before second maximum plasma drug level of the pulse release second time of about 2-5 hour, PC is about 1.5-3 hour arrival minimum after administration, and wherein the concentration of twice plasma drug level peak value should be close.Finally, after 8 hours, residue is no more than the plasma drug level of plasma peaks drug level 10% for the second time.
6, the two delivery formulations of product Zaleplon of the present invention; Test shows that whenever taking the two delivery formulations of Zaleplon can produce drug release twice in its human body; Its therapeutic effect is with to take ordinary preparation suitable at every turn; And can stablize control plasma drug level peak value, reduce side effect and addiction property that medicine brings, improve bioavailability of medicament to guarantee curative effect.
Below through test data beneficial effect of the present invention is described: the two release capsules of the Zaleplon of embodiment 1 preparation are adopted in test; Carry out influence factor's test (referring to 2010 editions two appendix XI X of Pharmacopoeia of People's Republic of China C) in the conventional medicine study on the stability; The prescription that embodies the two release capsules of Zaleplon of the present invention has high stability, compares with existing product and prior art to have unexpected technique effect.
Figure 913544DEST_PATH_IMAGE002
Figure 436930DEST_PATH_IMAGE003
Figure 679823DEST_PATH_IMAGE004
Release degree test about the invention described above product:
Leaching condition: sample 0～2 hour discharges in the hydrochloric acid solution of 0.1mol/L earlier, is transferred in 2～8 hours then in the release liquid of phosphate buffer of pH 6.8 to discharge, and the medium volume is 900ml; Adopt the device of dissolution second method, rotating speed is 75rpm, and temperature is 37 ℃, and detection method is a ultraviolet spectrophotometry.
Can show that by above-mentioned release degree test data result technical scheme of the present invention has the following advantages:
(1), the two release capsules of product Zaleplon of the present invention, adopt the method for galenic pharmacy to solve the inherent shortcoming of crude drug half-life too short (< 1 hour), increased the length of one's sleep, reduced clear-headed number of times and improved patient's therapeutic effect;
(2), the two release capsules of product Zaleplon of the present invention, the preparation process is simple, adopts fluidized-bed process; Under laboratory scale; Can accomplish the amplification production of 10000-30000 unit, production efficiency is high, can prepare the two release capsules of Zaleplon of 5-40mg different size;
(3), the two delivery formulations of product Zaleplon of the present invention; Show for dynamics research through the body giving drugs into nose; Have the bioavailability equivalence with ordinary preparation, do not produce the problem that reduces bioavailability because of the effect of part slowbreak, its pair discharges model and reduced blood plasma Chinese medicine peak concentration; Reduce the possibility that has side effects, take the compliance that has improved patient's medication once a day;
(4), the two release capsules of product Zaleplon of the present invention accelerated test in stability study is investigated 1, in 6 months property stability, medicament contg, related substance all in controlled range, influence factor's test in stability study simultaneously 1Investigation under high temperature, high humidity and the strong illumination condition, functional, suitability for industrialized production.
Indicate: 1Concrete test method and process are referring to " Pharmacopoeia of People's Republic of China 2010 editions " two appendix XI X C.
Four, description of drawings:
The release in vitro that the two release capsule preparations of Fig. 1 embodiment of the invention 1 preparation gained Zaleplon the are three batches line of writing music.
Five, the specific embodiment:
Further set forth the present invention below in conjunction with embodiment, but do not limit content of the present invention.
Embodiment 1:
The two release capsules of Zaleplon of the present invention comprise fast release micropill and slowbreak micropill, and the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 40% and 60%, and promptly fast release micropill and the slowbreak micropill mass ratio between the two is 2:3;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 16.1%, sucrose micropill 36.6%, filler mannitol 14.1%; Binding agent hypromellose 8.1%; Disintegrating agent A polyvinylpolypyrrolidone 2.0%, sealing coat filmogen hypromellose 13.9%, disintegrating agent B polyvinylpolypyrrolidone 6.9% and solubilizing agent A sodium lauryl sulphate 2.3%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.3%, sucrose micropill 32.4%; Filler mannitol 12.5%, binding agent hypromellose 7.1%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen hypromellose 12.3%; Disintegrating agent B polyvinylpolypyrrolidone 6.1%, solubilizing agent A sodium lauryl sulphate 2.0%, slowbreak material Aquacoat 11.5%.
Embodiment 2:
The method for preparing of the two release capsules of the foregoing description 1 Zaleplon, its detailed step is following:
At first carry pill core, prepare fast release micropill, prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last by carrying pill core according to the pharmaceutical formulation preparation;
(1), carry the preparation of pill core:
Carry the prescription of pill core: Zaleplon 92.4g; Sucrose micropill (30-40 order) 210g; Filler mannitol 80.85g, binding agent hypromellose 46.2g, disintegrating agent A polyvinylpolypyrrolidone 11.55g; 10% ethanol water 924g (this ethanol water is as solvent, solvent evaporation after this process);
Preparation process: at first under continuous stirring condition, hypromellose and mannitol joined mass percentage concentration and be in 10% the ethanol water and fully dissolve, be dissolved to clarification; The dissolving back adds raw material Zaleplon and disintegrating agent A polyvinylpolypyrrolidone, continues to stir 1-2h, crosses 40 eye mesh screens, obtains the medicated layer coating solution;
Get 30-40 purpose sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake as the ball core 3* h -1The medicated layer coating solution that obtains is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure is 1.0bar, improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets micropill; The micropill of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2) fast release micropill preparation:
The prescription of fast release micropill is for carrying pill core 400g, sealing coat filmogen hypromellose 72g, disintegrating agent B polyvinylpolypyrrolidone 36g, solubilizing agent A sodium lauryl sulphate 12g, deionized water 1080g;
Preparation process: under constantly stirring,, add disintegrating agent B polyvinylpolypyrrolidone after the dissolving, continue stirring 1h, cross 40 eye mesh screens, get the sealing coat coating solution with being dissolved to clarification in hypromellose and the sodium lauryl sulphate adding deionized water; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 40 ℃, the about 65m of adjustment intake 3* h -1The sealing coat coating solution that obtains is added to aerochamber atomizing coating through end spray mode with the flow velocity of 2ml/min with peristaltic pump; Atomizing pressure is 1.4bar, improves feed flow speed gradually to 6ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3) preparation of slowbreak micropill:
The prescription of slowbreak micropill is fast release micropill 300g, the Aquacoat 156g of 25% solid content, deionized water 156g;
Preparation process: get the Aquacoat of 25% solid content, under continuous stirring, add in the deionized water, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1, the slowbreak layer coating solution of obtaining, use peristaltic pump with end spray mode 1 ml/min pump into aerochamber atomizing coating, atomizing pressure is 1.6bar; Progressively improve feed flow speed to 4ml/min; Intact until the coating solution bag, coating finishes the back and places 50 ℃ of dry 2h in the convection oven, chooses the micropill in the 20-30 eye mesh screen scope; Inspection character and release degree promptly get the slowbreak micropill after qualified;
(4) fill of the two release capsules of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 2: 3 mixed after evenly, promptly get Zaleplon pair release capsules.
Through adjusting, in the present embodiment in the two release capsules of Zaleplon the ratio of each component be:
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 16.1%, sucrose micropill 36.6%, filler mannitol 14.1%; Binding agent hypromellose 8.1%; Disintegrating agent A polyvinylpolypyrrolidone 2.0%, sealing coat filmogen hypromellose 13.9%, disintegrating agent B polyvinylpolypyrrolidone 6.9% and solubilizing agent A sodium lauryl sulphate 2.3%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.3%, sucrose micropill 32.4%; Filler mannitol 12.5%, binding agent hypromellose 7.1%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen hypromellose 12.3%; Disintegrating agent B polyvinylpolypyrrolidone 6.1%, solubilizing agent A sodium lauryl sulphate 2.0%, slowbreak material Aquacoat 11.5%.
Embodiment 3:
The two release capsules of Zaleplon of the present invention comprise fast release micropill and slowbreak micropill, and the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 40% and 60%, and promptly fast release micropill and the slowbreak micropill mass ratio between the two is 2:3;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 19.1%; Sucrose micropill 43.3%, filler mannitol 16.7%, binding agent hypromellose 9.5%; Disintegrating agent A polyvinylpolypyrrolidone 2.4%, sealing coat filmogen Opadry 9.0%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.7%, sucrose micropill 33.3%; Filler mannitol 12.8%, binding agent hypromellose 7.3%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen Opadry 7.0%; Slowbreak material polyacrylic resin 16.3%, plasticizer Polyethylene Glycol 4.9%, antiplastering aid Pulvis Talci 1.6% and solubilizing agent B Polysorbate 0.3%.
Embodiment 4:
The method for preparing of the two release capsules of the foregoing description 3 Zaleplons, its detailed step is following:
At first carry pill core, prepare fast release micropill, prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last by carrying pill core according to the pharmaceutical formulation preparation;
(1), carry the pill core preparation:
Carry the pill core prescription: sucrose micropill (30-40 order) 210g, Zaleplon 92.4g, filler mannitol 80.85g, binding agent hypromellose 46.2g, disintegrating agent A polyvinylpolypyrrolidone 11.55g, 10% ethanol water 924g;
Preparation process: under constantly stirring, in 10% ethanol water, add hypromellose and mannitol, be dissolved to clarification, add Zaleplon and polyvinylpolypyrrolidone after the dissolving, continue to stir 1h, cross 40 eye mesh screens, get the medicated layer coating solution;
Get the sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure 1.0bar improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fine pellet core; The fine pellet core of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2), fast release micropill preparation:
Fast release micropill prescription: carry pill core 400g, Opadry 40g, deionized water 360g;
Preparation process: in deionized water, under stirring, add Opadry, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 45 ℃, the about 80m of intake 3* h -1, gained sealing coat coating solution is added to aerochamber atomizing coating, atomizing pressure 1.8bar with the flow velocity of 1.5ml/min with peristaltic pump earlier through end spray mode, improve feed flow speed gradually to 6ml/min, intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3), slowbreak micropill preparation:
Slowbreak micropill prescription: fast release micropill 250g, the polyacrylic resin aqueous dispersion 176g of 30% solid content, Pulvis Talci 15.8g, Polyethylene Glycol 5.3g, Polysorbate 1.1g, deionized water 211g;
Preparation process: deionized water is added Polyethylene Glycol and Polysorbate under continuous stirring, be dissolved to clarification, slowly add polyacrylic resin aqueous dispersion and Pulvis Talci, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1Get gained slowbreak layer coating solution and pump into aerochamber atomizing coating with peristaltic pump with end spray mode 1.5ml/min, atomizing pressure is 1.4bar, and it is intact to 5ml/min to the coating solution bag progressively to improve feed flow speed; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven; Choose the micropill in the 20-30 eye mesh screen scope, inspection character and release degree promptly get the slowbreak micropill after qualified;
(4), the two release capsule fills of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 2: 3 mixed after evenly, promptly get Zaleplon pair release capsules.
Through adjusting, in the present embodiment in the two release capsules of Zaleplon the ratio of each component be:
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 19.1%; Sucrose micropill 43.3%, filler mannitol 16.7%, binding agent hypromellose 9.5%; Disintegrating agent A polyvinylpolypyrrolidone 2.4%, sealing coat filmogen Opadry 9.0%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.7%, sucrose micropill 33.3%; Filler mannitol 12.8%, binding agent hypromellose 7.3%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen Opadry 7.0%; Slowbreak material polyacrylic resin 16.3%, plasticizer Polyethylene Glycol 4.9%, antiplastering aid Pulvis Talci 1.6% and solubilizing agent B Polysorbate 0.3%.
Embodiment 5:
The two release capsules of Zaleplon of the present invention comprise fast release micropill and slowbreak micropill, and the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 40% and 60%, and promptly fast release micropill and the slowbreak micropill mass ratio between the two is 2:3;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 13.8%; Sucrose micropill 31.3%, filler lactose 12.0%, binding agent hypromellose 6.9%; Disintegrating agent A low-substituted hydroxypropyl cellulose 2.7%, sealing coat filmogen Opadry 33.3%;
With respect to slowbreak part in the two release capsules of Zaleplon; Said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 12.2%, sucrose micropill 27.6%, filler lactose 10.7%; Binding agent hypromellose 6.1%; Disintegrating agent A low-substituted hydroxypropyl cellulose 2.4%, sealing coat filmogen Opadry 29.5%, slowbreak material ethyl cellulose 11.5%.
Embodiment 6:
The method for preparing of the two release capsules of the foregoing description 5 Zaleplons: its detailed step is following:
At first carry pill core, prepare fast release micropill, prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last by carrying pill core according to the pharmaceutical formulation preparation;
(1), carry the pill core preparation:
Carry the pill core prescription: Zaleplon 92.4g, blank sucrose micropill (30/40 order) 210g, filler lactose 80.85g, binding agent hypromellose 46.2g, disintegrating agent A low-substituted hydroxypropyl cellulose 18.25g, 10% ethanol water 924g;
The preparation process: adding hypromellose and lactose dissolve in 10% ethanol water constantly stirring down; Be dissolved to clarification, the dissolving back adds 30-40 purpose Zaleplon and low-substituted hydroxypropyl cellulose, continues to stir 1h; Cross 40 eye mesh screens, get the medicated layer coating solution;
Get blank sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure is 1.0bar, improves feed flow speed gradually to 6ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets the medicine carrying micropill; The micropill of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2), fast release micropill preparation:
Fast release micropill prescription: carry pill core 400g, Opadry 200g, deionized water 1800g;
Preparation process: in deionized water, under stirring, add Opadry, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 45 ℃, the about 80m of intake 3* h -1, gained sealing coat coating solution is added to aerochamber atomizing coating, atomizing pressure 1.8bar with the flow velocity of 1.5ml/min with peristaltic pump earlier through end spray mode, improve feed flow speed gradually to 8ml/min, intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3) slowbreak micropill preparation:
Slowbreak micropill prescription: fast release micropill 300g, the Aquacoat 156g of 25% solid content, deionized water 156g;
Preparation process: Aquacoat is added under stirring in the deionized water, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution;
Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1, get gained slowbreak layer coating solution, pump into aerochamber atomizing coating with peristaltic pump with end spray mode 1ml/min; Atomizing pressure is 1.6bar, progressively improves feed flow speed to 4ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven; Choose the micropill in the 20-30 eye mesh screen scope, inspection character and release degree promptly get the slowbreak micropill after qualified;
(4) the two release capsule fills of Zaleplon
Fast release micropill and slowbreak micropill are packed into capsule after by 2: 3 mass ratio (in Zaleplon) mix homogeneously, promptly get the two release capsules of Zaleplon.
Through adjusting, in the present embodiment in the two release capsules of Zaleplon the ratio of each component be:
The percentage by weight of each component is respectively in the fast release micropill: Zaleplon 13.8%; Sucrose micropill 31.3%, filler lactose 12.0%, binding agent hypromellose 6.9%; Disintegrating agent A low-substituted hydroxypropyl cellulose 2.7%, sealing coat filmogen Opadry 33.3%;
The percentage by weight of each component is respectively in the slowbreak micropill: Zaleplon 12.2%; Sucrose micropill 27.6%; Filler lactose 10.7%, binding agent hypromellose 6.1%, disintegrating agent A low-substituted hydroxypropyl cellulose 2.4%; Sealing coat filmogen Opadry 29.5%, slowbreak material ethyl cellulose 11.5%.
Embodiment 7:
The method for preparing of the two release capsules of Zaleplon of the present invention, its detailed step is following:
At first carry pill core, prepare fast release micropill, prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last by carrying pill core according to the pharmaceutical formulation preparation;
(1) carry the pill core preparation:
Carry the pill core prescription: Zaleplon 92.4g, blank sucrose micropill (30/40 order) 210g, filler mannitol 80.85g, binding agent hypromellose 46.2g, disintegrating agent A low-substituted hydroxypropyl cellulose 11.55g, 10% ethanol water 924g;
Preparation process: under agitation in 10% ethanol water, add hypromellose and mannitol, be dissolved to clarification, add Zaleplon and polyvinylpolypyrrolidone after the dissolving, continue to stir 1h, cross 40 eye mesh screens, get the medicated layer coating solution;
Get blank sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure is 1.0bar, improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets the medicine carrying micropill; The medicine carrying micropill of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2), fast release micropill preparation:
Fast release micropill prescription: carry pill core 400g, Opadry 84g, polyvinylpolypyrrolidone 36g, deionized water 1080g;
Preparation process: under agitation in deionized water, add Opadry, be dissolved to clarification, add polyvinylpolypyrrolidone then, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution;
Get and carry a pill core and put into fluid bed, regulate temperature of charge to 40 ℃, the about 65m of adjustment intake 3* h -1Gained sealing coat coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 2ml/min with peristaltic pump; Atomizing pressure is 1.6bar, improves feed flow speed gradually to 6ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3) slowbreak micropill preparation:
Slowbreak micropill prescription: fast release micropill 300g, the Aquacoat 240g of 25% solid content, hypromellose 1.2g, deionized water 240g;
Preparation process: deionized water is added in the hypromellose under stirring, stir to clarify, obtain the hypromellose aqueous solution; Other gets Aquacoat, under stirring, adds in the gained hypromellose aqueous solution, continues to stir 1h, crosses 40 eye mesh screens, gets slowbreak layer coating solution;
Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1, get gained slowbreak layer coating solution, pump into aerochamber atomizing coating with peristaltic pump with end spray mode 1.5ml/min; Atomizing pressure is 1.6bar, progressively improves feed flow speed to 5ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven; Choose the micropill in the 20-30 eye mesh screen scope, inspection character and release degree promptly get the slowbreak micropill after qualified;
(4) the two release capsule fills of Zaleplon
Fast release micropill and slowbreak micropill are packed into capsule after by 2: 3 mass ratio (in Zaleplon) mix homogeneously, promptly get the two release capsules of Zaleplon.
Embodiment 8:
The method for preparing of the two release capsules of Zaleplon of the present invention, its detailed step is following:
At first carry pill core, prepare fast release micropill, prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last by carrying pill core according to the pharmaceutical formulation preparation;
(1), carry the pill core preparation:
Carry the pill core prescription: microcrystalline Cellulose micropill 300g, Zaleplon 100g, filler lactose 100g, binding agent hydroxypropyl cellulose 50g, disintegrating agent A cross-linking sodium carboxymethyl cellulose 10g, 50% ethanol water 1000g;
The preparation process: under constantly stirring, in 50% ethanol water, add hydroxypropyl cellulose and lactose, be dissolved to clarification, the Zaleplon and the cross-linking sodium carboxymethyl cellulose that add after the dissolving continue to stir 1h, cross 40 eye mesh screens, get the medicated layer coating solution;
Get the microcrystalline Cellulose micropill and put into fluid bed, regulate temperature of charge to 45 ℃, the about 60m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure 1.2bar improves feed flow speed gradually to 10ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fine pellet core; The fine pellet core of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2), fast release micropill preparation:
Fast release micropill prescription: carry pill core 400g, Opadry 40g, deionized water 360g;
Preparation process: in deionized water, under stirring, add Opadry, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 45 ℃, the about 85m of intake 3* h -1, gained sealing coat coating solution is added to aerochamber atomizing coating, atomizing pressure 1.6bar with the flow velocity of 1.5ml/min with peristaltic pump earlier through end spray mode, improve feed flow speed gradually to 5ml/min, intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3), slowbreak micropill preparation:
Slowbreak micropill prescription: fast release micropill 250g, the polyacrylic resin aqueous dispersion 200g Pulvis Talci 25g of 30% solid content, triethyl citrate 10g, deionized water 200g;
Preparation process: deionized water is added triethyl citrate under continuous stirring, be dissolved to clarification, slowly add polyacrylic resin aqueous dispersion and Pulvis Talci, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1Get gained slowbreak layer coating solution and pump into aerochamber atomizing coating with peristaltic pump with end spray mode 1.5ml/min, atomizing pressure is 1.4bar, and it is intact to 5ml/min to the coating solution bag progressively to improve feed flow speed; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven; Choose the micropill in the 20-30 eye mesh screen scope, inspection character and release degree promptly get the slowbreak micropill after qualified;
(4), the two release capsule fills of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 1: 1 mixed after evenly, promptly get Zaleplon pair release capsules.
Embodiment 9:
The method for preparing of the two release capsules of Zaleplon of the present invention, its detailed step is following:
At first carry pill core, prepare fast release micropill, prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last by carrying pill core according to the pharmaceutical formulation preparation;
(1), carry the pill core preparation:
Carry the pill core prescription: microcrystalline Cellulose micropill 300g, Zaleplon 100g, filler mannitol 100g, binding agent hydroxypropyl cellulose 50g, disintegrating agent A polyvinylpolypyrrolidone 10g, 20% ethanol water 950g;
The preparation process: under constantly stirring, in 20% ethanol water, add hydroxypropyl cellulose and mannitol, be dissolved to clarification, the Zaleplon and the polyvinylpolypyrrolidone that add after the dissolving continue to stir 1h, cross 40 eye mesh screens, get the medicated layer coating solution;
Get the microcrystalline Cellulose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure 1.0bar improves feed flow speed gradually to 10ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fine pellet core; The fine pellet core of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2) fast release micropill preparation:
The prescription of fast release micropill is for carrying pill core 400g, sealing coat filmogen hydroxypropyl cellulose 80g, disintegrating agent B polyvinylpolypyrrolidone 40g, solubilizing agent A sodium lauryl sulphate 20g, deionized water 1000g;
Preparation process: under constantly stirring,, add disintegrating agent B polyvinylpolypyrrolidone after the dissolving, continue stirring 1h, cross 40 eye mesh screens, get the sealing coat coating solution with being dissolved to clarification in hydroxypropyl cellulose and the sodium lauryl sulphate adding deionized water; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 40 ℃, the about 65m of adjustment intake 3* h -1The sealing coat coating solution that obtains is added to aerochamber atomizing coating through end spray mode with the flow velocity of 2ml/min with peristaltic pump; Atomizing pressure is 1.4bar, improves feed flow speed gradually to 6ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3) preparation of slowbreak micropill:
The prescription of slowbreak micropill is fast release micropill 300g, the Aquacoat 180g of 25% solid content, deionized water 180g;
Preparation process: get the Aquacoat of 25% solid content, under continuous stirring, add in the deionized water, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1, the slowbreak layer coating solution of obtaining, use peristaltic pump with end spray mode 1 ml/min pump into aerochamber atomizing coating, atomizing pressure is 1.6bar; Progressively improve feed flow speed to 4ml/min; Intact until the coating solution bag, coating finishes the back and places 50 ℃ of dry 2h in the convection oven, chooses the micropill in the 20-30 eye mesh screen scope; Inspection character and release degree promptly get the slowbreak micropill after qualified;
(4) fill of the two release capsules of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 1: 1 mixed after evenly, promptly get Zaleplon pair release capsules.
Embodiment 10:
The method for preparing of the two release capsules of Zaleplon of the present invention, its detailed step is following:
At first carry pill core, prepare fast release micropill, prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last by carrying pill core according to the pharmaceutical formulation preparation;
(1), carry the pill core preparation:
Carry the pill core prescription: sucrose-starch micropill (30-40 order) 250g, Zaleplon 100g, filler mannitol 120g, binding agent hydroxypropyl cellulose 40g, disintegrating agent A polyvinylpolypyrrolidone 10g, purified water 900g;
Preparation process: under constantly stirring, in 10% ethanol water, add hydroxypropyl cellulose and mannitol, be dissolved to clarification, add Zaleplon and polyvinylpolypyrrolidone after the dissolving, continue to stir 1h, cross 40 eye mesh screens, get the medicated layer coating solution;
Get sucrose-starch micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure 1.0bar improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fine pellet core; The fine pellet core of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2), fast release micropill preparation:
Fast release micropill prescription: carry pill core 400g, hydroxypropyl cellulose 40g, polyvinylpolypyrrolidone 4g, deionized water 400g;
Preparation process: under agitation in deionized water, add hydroxypropyl cellulose, be dissolved to clarification, add polyvinylpolypyrrolidone then, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution;
Get and carry a pill core and put into fluid bed, regulate temperature of charge to 40 ℃, the about 65m of adjustment intake 3* h -1Gained sealing coat coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 2ml/min with peristaltic pump; Atomizing pressure is 1.6bar, improves feed flow speed gradually to 6ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3), slowbreak micropill preparation:
Slowbreak micropill prescription: fast release micropill 250g, polyacrylic resin 75g, Pulvis Talci 30g, triethyl citrate 15g, 90% ethanol water 900g;
Preparation process: 90% ethanol water is added triethyl citrate and polyacrylic resin under continuous stirring, be dissolved to clarification, slowly add Pulvis Talci, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 30 ℃, the about 70m of adjustment air intake flow 3* h -1Get gained slowbreak layer coating solution and pump into aerochamber atomizing coating with peristaltic pump with end spray mode 2ml/min, atomizing pressure is 1.8bar, and it is intact to 10ml/min to the coating solution bag progressively to improve feed flow speed; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven; Choose the micropill in the 20-30 eye mesh screen scope, inspection character and release degree promptly get the slowbreak micropill after qualified;
(4), the two release capsule fills of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 3: 5 mixed after evenly, promptly get Zaleplon pair release capsules.
The release degree test of the two release capsules of the foregoing description 1～10 products obtained therefrom Zaleplon:
As specimen, degree of release is tested with the two delivery formulations of prepared Zaleplon among the embodiment 2, and method is following:
Get specimen, make an experiment (2010 editions two appendix X D of Chinese Pharmacopoeia, second method), adopt dissolution method second subtraction unit according to the drug release determination method; Rotating speed is 75rpm, and temperature is 37 ℃, and sample discharged in the hydrochloric acid solution of 0.1mol/L 900ml in 0～2 hour; 2 hours; Add the phosphate buffer 900ml that is preheated to 37 ℃ of pH 6.8 immediately, rotating speed is constant, and sample discharged in the phosphate buffer of these pH 6.8 900ml in 2～8 hours; Detection method is a ultraviolet spectrophotometry, and sampling time point is: 45 minutes, 120 minutes, 240 minutes, 360 minutes.It is an amount of to get solution at each time point, filters, and gets subsequent filtrate as need testing solution, adopts external standard method to calculate different burst sizes constantly.
The result shows: the two delivery formulations of the Zaleplon that embodiment 1 makes about 40%, 45 minute to 2 hours accumulative total of 45 minutes cumulative release amounts burst size in acid is constant basically, and 2 hours cumulative release degree reach 99.6% in the buffer of pH=6.8.
The two release capsule preparations of product Zaleplon that embodiment 2,3,4,5,6 and 7 is prepared, under the same test condition, result of the test is identical with embodiment 1, all meets the requirements.

Claims (10)

1. the two release capsules of Zaleplon comprise fast release micropill and slowbreak micropill, and it is characterized in that: the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 20～60% and 80～40%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 5～35%, blank micropill 10～60%, filler 0～30%; Binding agent 1～15%; Disintegrating agent A 0.5～5%, sealing coat filmogen 0～35%, disintegrating agent B 0～8% and solubilizing agent A 0～3%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 5～35%, blank micropill 10～50%; Filler 0～30%, binding agent 1～15%, disintegrating agent A 0.5～5%; Sealing coat filmogen 0～30%, disintegrating agent B 0～8%, solubilizing agent A 0～3%; Slowbreak material 5～30%, plasticizer 0～5%, antiplastering aid 0～10% and solubilizing agent B 0～1%.
2. the two release capsules of Zaleplon according to claim 1 is characterized in that said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%; Blank micropill 20～50%; Filler 5～20%, binding agent 5～15%, disintegrating agent A 1～5%; Sealing coat filmogen 5～20%, disintegrating agent B 0～7% and solubilizing agent A 0～3%;
Said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%, blank micropill 20～50%, filler 5～20%; Binding agent 5～15%, disintegrating agent A 1～5%, sealing coat filmogen 5～15%; Disintegrating agent B 0～7%, solubilizing agent A 0～3%, slowbreak material 8～25%; Plasticizer 0～3%, antiplastering aid 0～8% and solubilizing agent B 0～1%.
3. the two release capsules of Zaleplon according to claim 1 and 2, it is characterized in that: said blank micropill is any one or more in sucrose micropill, microcrystalline Cellulose micropill, starch micropill, lactose-microcrystalline Cellulose micropill, starch-microcrystalline Cellulose micropill, the sucrose-starch micropill;
Said filler is any one or more in sucrose, lactose, mannitol, starch, microcrystalline Cellulose, Sargassum polysaccharides and the chitosan;
Said binding agent is any one or more in water, dehydrated alcohol, water and ethanol mixing, Opadry, hypromellose, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol and the sodium carboxymethyl cellulose;
Said disintegrating agent A is any one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the carboxymethylcellulose calcium;
Said sealing coat filmogen is any one or more in Opadry, hypromellose, hydroxypropyl cellulose, polyvidone and the polyvinyl alcohol;
Said disintegrating agent B is any one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the carboxymethylcellulose calcium;
Said solubilizing agent A is any one or more in sodium lauryl sulphate, sorbitan fatty acid ester, poloxamer, dodecyl sodium sulfate, Polysorbate, ursodesoxycholic acid, lithium dodecyl sulfate and the Polysorbate;
Said slowbreak material is that ethyl cellulose, hypromellose, polyacrylic resin, polyacrylic resin aqueous dispersion, Aquacoat, hydroxypropyl cellulose, hydroxyethyl-cellulose acetyl cellulose, Lac, cellulose acetate-phthalate ester, cellulose acetate phthalate ester, vinyl acetate phthalate ester, hypromellose phthalate ester, refined gram are suitable, in hypromellose succinate, polylactic acid and the palm wax any one or more;
Said plasticizer is any one or more in triethyl citrate, ATEC, tributyl 2-acetylcitrate, dibutyl sebacate, glyceryl triacetate, Polyethylene Glycol, diethyl phthalate, dibutyl phthalate, tristerin, tributyl citrate, diethyl succinate, fractionated coconut oil and the propylene glycol;
Said antiplastering aid is any one or more in Pulvis Talci, colloidal silica, magnesium stearate, calcium stearate, magnesium silicate and the glyceryl monostearate;
Said solubilizing agent B is any one or more in sodium lauryl sulphate, sorbitan fatty acid ester, poloxamer, dodecyl sodium sulfate, Polysorbate, ursodesoxycholic acid, lithium dodecyl sulfate, Polysorbate, Polyethylene Glycol and the hypromellose.
4. the two release capsules of Zaleplon according to claim 3; It is characterized in that: it is the sucrose micropill that said fast release micropill supplementary material is formed the empty micropill, and filler is a mannitol, and binding agent is a hypromellose; Disintegrating agent A is a polyvinylpolypyrrolidone; The sealing coat filmogen is hypromellose or Opadry, and disintegrating agent B is a polyvinylpolypyrrolidone, and solubilizing agent A is a sodium lauryl sulphate;
It is the sucrose micropill that said slowbreak micropill supplementary material is formed the empty micropill, and filler is a mannitol, and binding agent is a hypromellose; Disintegrating agent A is a polyvinylpolypyrrolidone; The sealing coat filmogen is hypromellose or Opadry, and disintegrating agent B is a polyvinylpolypyrrolidone, and solubilizing agent A is a sodium lauryl sulphate; The slowbreak material is polyacrylic resin, polyacrylic resin aqueous dispersion or Aquacoat; Plasticizer is Polyethylene Glycol or triethyl citrate, and antiplastering aid is a Pulvis Talci, and solubilizing agent B is Polysorbate or hypromellose.
5. the two release capsules of Zaleplon according to claim 4, it is characterized in that: the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 20～60% and 80～40%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%, sucrose micropill 20～50%, filler mannitol 5～20%; Binding agent hypromellose 5～15%; Disintegrating agent A polyvinylpolypyrrolidone 1～5%, sealing coat filmogen hypromellose or Opadry 5～20%, disintegrating agent B polyvinylpolypyrrolidone 0～7% and solubilizing agent A sodium lauryl sulphate 0～3%;
With respect to slowbreak part in the two release capsules of Zaleplon; Said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 10～30%, sucrose micropill 20～50%, filler mannitol 5～20%; Binding agent hypromellose 5～15%; Disintegrating agent A polyvinylpolypyrrolidone 1～5%, sealing coat filmogen hypromellose or Opadry 5～15%, disintegrating agent B polyvinylpolypyrrolidone 0～7%; Solubilizing agent A sodium lauryl sulphate 0～3%; Slowbreak material polyacrylic resin, polyacrylic resin aqueous dispersion or Aquacoat 8～25%, plasticizer Polyethylene Glycol or triethyl citrate 0～3%, antiplastering aid Pulvis Talci 0～8% and solubilizing agent B Polysorbate or hypromellose 0～1%.
6. the two release capsules of Zaleplon according to claim 5, it is characterized in that: the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 40% and 60%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 16.1%, sucrose micropill 36.6%, filler mannitol 14.1%; Binding agent hypromellose 8.1%; Disintegrating agent A polyvinylpolypyrrolidone 2.0%, sealing coat filmogen hypromellose 13.9%, disintegrating agent B polyvinylpolypyrrolidone 6.9% and solubilizing agent A sodium lauryl sulphate 2.3%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.3%, sucrose micropill 32.4%; Filler mannitol 12.5%, binding agent hypromellose 7.1%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen hypromellose 12.3%; Disintegrating agent B polyvinylpolypyrrolidone 6.1%, solubilizing agent A sodium lauryl sulphate 2.0%, slowbreak material Aquacoat 11.5%.
7. the two release capsules of Zaleplon according to claim 5, it is characterized in that: the two shared weight percentage of said fast release micropill and slowbreak micropill is respectively 40% and 60%;
With respect to immediate release section in the two release capsules of Zaleplon; Said fast release micropill is made up of the supplementary material of following percentage by weight: Zaleplon 19.1%; Sucrose micropill 43.3%, filler mannitol 16.7%, binding agent hypromellose 9.5%; Disintegrating agent A polyvinylpolypyrrolidone 2.4%, sealing coat filmogen Opadry 9.0%;
With respect to slowbreak part in the two release capsules of Zaleplon, said slowbreak micropill is made up of the supplementary material of following percentage by weight: Zaleplon 14.7%, sucrose micropill 33.3%; Filler mannitol 12.8%, binding agent hypromellose 7.3%, disintegrating agent A polyvinylpolypyrrolidone 1.8%; Sealing coat filmogen Opadry 7.0%; Slowbreak material polyacrylic resin 16.3%, plasticizer Polyethylene Glycol 4.9%, antiplastering aid Pulvis Talci 1.6% and solubilizing agent B Polysorbate 0.3%.
8. the two release capsules of Zaleplon according to claim 1 is characterized in that: the effective dose of the Zaleplon in the two release capsules of said Zaleplon is 5～40mg.
9. the method for preparing of the two release capsules of the described Zaleplon of claim 6; It is characterized in that: at first pill core is carried in preparation; Prepare fast release micropill by carrying pill core; Prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last;
(1), carry the preparation of pill core:
The prescription that carries pill core is Zaleplon 92.4g, sucrose micropill (30-40 order) 210g, filler mannitol 80.85g, binding agent hypromellose 46.2g, disintegrating agent A polyvinylpolypyrrolidone 11.55g, 10% ethanol water 924g;
Preparation process: at first under continuous stirring condition, hypromellose and mannitol joined mass percentage concentration and be in 10% the ethanol water and fully dissolve, be dissolved to clarification; The dissolving back adds raw material Zaleplon and disintegrating agent A polyvinylpolypyrrolidone, continues to stir 1-2h, crosses 40 eye mesh screens, obtains the medicated layer coating solution;
Get 30-40 purpose sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake as the ball core 3* h -1The medicated layer coating solution that obtains is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure is 1.0bar, improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets micropill; The micropill of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2) fast release micropill preparation:
The prescription of fast release micropill is for carrying pill core 400g, sealing coat filmogen hypromellose 72g, disintegrating agent B polyvinylpolypyrrolidone 36g, solubilizing agent A sodium lauryl sulphate 12g, deionized water 1080g;
Preparation process: under constantly stirring,, add disintegrating agent B polyvinylpolypyrrolidone after the dissolving, continue stirring 1h, cross 40 eye mesh screens, get the sealing coat coating solution with being dissolved to clarification in hypromellose and the sodium lauryl sulphate adding deionized water; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 40 ℃, the about 65m of adjustment intake 3* h -1The sealing coat coating solution that obtains is added to aerochamber atomizing coating through end spray mode with the flow velocity of 2ml/min with peristaltic pump; Atomizing pressure is 1.4bar, improves feed flow speed gradually to 6ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3) preparation of slowbreak micropill:
The prescription of slowbreak micropill is fast release micropill 300g, the Aquacoat 156g of 25% solid content, deionized water 156g;
Preparation process: get the Aquacoat of 25% solid content, under continuous stirring, add in the deionized water, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1, the slowbreak layer coating solution of obtaining, use peristaltic pump with end spray mode 1 ml/min pump into aerochamber atomizing coating, atomizing pressure is 1.6bar; Progressively improve feed flow speed to 4ml/min; Intact until the coating solution bag, coating finishes the back and places 50 ℃ of dry 2h in the convection oven, chooses the micropill in the 20-30 eye mesh screen scope; Inspection character and release degree promptly get the slowbreak micropill after qualified;
(4) fill of the two release capsules of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 2: 3 mixed after evenly, promptly get Zaleplon pair release capsules.
10. the method for preparing of the two release capsules of the described Zaleplon of claim 7; It is characterized in that: at first pill core is carried in preparation; Prepare fast release micropill by carrying pill core; Prepare the slowbreak micropill by fast release micropill then, with the fast release micropill and the slowbreak micropill difference filled capsules of preparation, obtain the two release capsules of Zaleplon at last;
(1), carry the pill core preparation:
Carry the pill core prescription: sucrose micropill (30-40 order) 210g, Zaleplon 92.4g, filler mannitol 80.85g, binding agent hypromellose 46.2g, disintegrating agent A polyvinylpolypyrrolidone 11.55g, 10% ethanol water 924g;
Preparation process: under constantly stirring, in 10% ethanol water, add hypromellose and mannitol, be dissolved to clarification, add Zaleplon and polyvinylpolypyrrolidone after the dissolving, continue to stir 1h, cross 40 eye mesh screens, get the medicated layer coating solution;
Get the sucrose micropill and put into fluid bed, regulate temperature of charge to 40 ℃, the about 50m of adjustment intake 3* h -1Gained medicated layer coating solution is added to aerochamber atomizing coating through end spray mode with the flow velocity of 3ml/min with peristaltic pump; Atomizing pressure 1.0bar improves feed flow speed gradually to 9ml/min, and is intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fine pellet core; The fine pellet core of getting the 24-35 mesh sieve carries out uniformity of dosage units and water content inspection, qualified after, pill core is subsequent use as carrying;
(2), fast release micropill preparation:
Fast release micropill prescription: carry pill core 400g, Opadry 40g, deionized water 360g;
Preparation process: in deionized water, under stirring, add Opadry, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution; Get and carry a pill core and put into fluid bed, regulate temperature of charge to 45 ℃, the about 80m of intake 3* h -1, gained sealing coat coating solution is added to aerochamber atomizing coating, atomizing pressure 1.8bar with the flow velocity of 1.5ml/min with peristaltic pump earlier through end spray mode, improve feed flow speed gradually to 6ml/min, intact until the coating solution bag; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven, promptly gets fast release micropill;
(3), slowbreak micropill preparation:
Slowbreak micropill prescription: fast release micropill 250g, the polyacrylic resin aqueous dispersion 176g of 30% solid content, Pulvis Talci 15.8g, Polyethylene Glycol 5.3g, Polysorbate 1.1g, deionized water 211g;
Preparation process: deionized water is added Polyethylene Glycol and Polysorbate under continuous stirring, be dissolved to clarification, slowly add polyacrylic resin aqueous dispersion and Pulvis Talci, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution; Get fast release micropill and place fluid bed, regulate temperature of charge to 35 ℃, the about 80m of adjustment air intake flow 3* h -1Get gained slowbreak layer coating solution and pump into aerochamber atomizing coating with peristaltic pump with end spray mode 1.5ml/min, atomizing pressure is 1.4bar, and it is intact to 5ml/min to the coating solution bag progressively to improve feed flow speed; Coating finishes the back and places 50 ℃ of dry 2h in the convection oven; Choose the micropill in the 20-30 eye mesh screen scope, inspection character and release degree promptly get the slowbreak micropill after qualified;
(4), the two release capsule fills of Zaleplon:
In Zaleplon, fast release micropill and slowbreak micropill are packed into capsule by 2: 3 mixed after evenly, promptly get Zaleplon pair release capsules.
CN2012103665328A 2012-09-28 2012-09-28 Zaleplon double-release capsule and preparation method thereof Pending CN102824331A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104382882A (en) * 2014-11-27 2015-03-04 河南中帅医药科技股份有限公司 PH-independent zaleplon dipulse release capsule and method for preparing same
WO2019071270A1 (en) * 2017-10-06 2019-04-11 Adare Pharmaceuticals, Inc. Pharmaceutical compositions
WO2022019948A1 (en) * 2020-07-21 2022-01-27 Aura7 USA Inc. Activated carbon balls and method for producing thereof

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CN1738608A (en) * 2002-11-15 2006-02-22 依兰制药公司 Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders
CN101076321A (en) * 2004-10-28 2007-11-21 雅戈泰克股份公司 Dosage form time lagged of drugs for the therapy of insomnia

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CN1738608A (en) * 2002-11-15 2006-02-22 依兰制药公司 Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders
CN101076321A (en) * 2004-10-28 2007-11-21 雅戈泰克股份公司 Dosage form time lagged of drugs for the therapy of insomnia

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104382882A (en) * 2014-11-27 2015-03-04 河南中帅医药科技股份有限公司 PH-independent zaleplon dipulse release capsule and method for preparing same
CN104382882B (en) * 2014-11-27 2018-01-19 河南中帅医药科技股份有限公司 A kind of Zaleplon dipulse release capsule of non-TCP friendly flow and preparation method thereof
WO2019071270A1 (en) * 2017-10-06 2019-04-11 Adare Pharmaceuticals, Inc. Pharmaceutical compositions
WO2022019948A1 (en) * 2020-07-21 2022-01-27 Aura7 USA Inc. Activated carbon balls and method for producing thereof

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