CN1188131C - Orally taken pulsed releasing system of phenyl diazepine medicine and its prepn. - Google Patents
Orally taken pulsed releasing system of phenyl diazepine medicine and its prepn. Download PDFInfo
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- CN1188131C CN1188131C CN 02137935 CN02137935A CN1188131C CN 1188131 C CN1188131 C CN 1188131C CN 02137935 CN02137935 CN 02137935 CN 02137935 A CN02137935 A CN 02137935A CN 1188131 C CN1188131 C CN 1188131C
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Abstract
The present invention discloses a pulsed releasing system of phenyl diazepine medicine, which is used for treating early awakening patients and comprises diazepam, estazolam and triazolam, and a preparation method thereof. The preparation is prepared by mixing a basic remedy, sodium dodecyl sulfate as a surface active agent, and other auxiliary materials to prepare a tablet core which is suspended in ethanol by acrylic resin polymers, hydrophobic polymers and a plasticizing agent, and coated. The present invention has the advantages of good preparation bioavailability and preparation method reproducibility, no side effect of somnolence sensation, simple technology and low production cost, can ensure exact medicine doses and is favorable to commercial processes.
Description
Technical field
The present invention relates to oral pulsed release system of benzodiazepine and preparation method thereof, especially treat the oral pulsed release system and preparation method thereof of diazepam, estazolam and the triazolam medicine of early awakening.
Background technology
Calmness in the benzodiazepine, hypnosis, medicine antianxity comprise diazepam, estazolam, triazolam etc., and its common trait is, and be almost insoluble in water, and certain solubility is arranged in the stomach, absorb rapidly in intestinal, and the effective dose of clinical practice is little.
Along with the quickening of work rhythm and the growth at age, the middle-aged and elderly people early awakening is a kind of common disease.Use treatments such as diazepam, estazolam, triazolam clinically.For example: clinical calmness, hypnosis, the choice drug diazepam antianxity of being used for, oral absorption is rapid, promptly reaches peak plasma concentration, and has ordinary tablet and two kinds of dosage forms of slow releasing tablet now in 0.5～1 hour.The diazepam conventional tablet is taken before sleeping usually, because this drug treating time is short, often can not satisfy the patient's that has difficulty in going to sleep behind the early awakening of morning 3～4 requirement.Get up and take medicine once more so that patient often needs midnight.For this reason, U.S. Roche company develops the diazepam slow releasing capsule of having gone on the market, and commodity are called Valrelease, every contains principal agent 15mg, 1～2 of day clothes, and its average out to peak time is 5.3 hours, major advantage is that release is lasting, can keep long-acting, and patient need not frequent medication.But these side effects of pharmaceutical drugs are obvious, and the patient had very heavy drowsiness sense in promptly second day, thereby influence the operate as normal on daytime.Therefore, diazepam ordinary tablet of Shi Yonging and external commercially available slow releasing capsule clinically, not only to treating easily sleeping but morning early awakening patient curative effect relatively poor, and the shortcoming that can not ignore is arranged in actual use.
Oral pulsed release system be development in recent years get up according to physiology with the treatment needs novel form of release at regular time and quantity, can be divided into osmotic pumps pulse system, coating pulse system and commutator pulse plug capsule.After the coating pulse system is meant that the patient takes preparation, does not present zero level immediately and discharge, but just begin release after a tangible interval is arranged, one " time lag " promptly arranged.Film packaging technique in the coating pulse system, sugar grain commonly used is made core, behind the outsourcing medicine, wrap the disintegrate material again, wrap the insoluble coating material that has porogen at last and make release-controlled film (referring to Orally taken pulsed and time-controlled explosion system, " foreign medical science pharmacy fascicle " 1999, the 26th the 1st phase of volume: 33 pages).This kind film art for coating is to the specification requirement height, during the parcel medicine, is difficult to control the outer dose of wrapping up on sugar nuclear, especially strong and medicine that effective dose is little for some pharmacological actions, and this method practice in pharmaceuticals industry has certain difficulty.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of oral pulsed release system for the treatment of the slightly solubility benzodiazepine of early awakening, the oral back of said preparation medicine does not discharge immediately, but lag behind when certain, medicine discharges from tablet rapidly, and blood drug level presents the pulsed peak value.Patient can release a certain dose drug in early awakening prolapse at night as long as taking a medicine at bedtime, and plays sedative-hypnotic effect, makes patient be in sleep state once more.The patient both need not to get up midnight and had taken medicine once more, did not also have the hysteresis drug effect of slow releasing tablet, as drowsiness etc., can not influence work in second day.
That is to say that the Orally taken pulsed release preparation of slightly solubility benzodiazepine of the present invention discharges after can postponing the quite a while after the patient takes again, still, in case discharge, just discharges whole doses rapidly, thereby has best bioavailability.And drug release rate is not subjected to the influence of label pressure, can guarantee the stable of the quality of the pharmaceutical preparations.
In addition, the present invention's expectation reaches the purpose of utilizing minimum dose effectively to treat by medicine release at regular time and quantity.
If desired, the Orally taken pulsed release preparation of slightly solubility benzodiazepine of the present invention can with the ordinary tablet administering drug combinations, ordinary tablet makes the difficulty falling asleep, and the person can fall asleep as early as possible, the person slept peacefully to early morning and Orally taken pulsed release preparation of the present invention can make the early awakening.
The technical problem to be solved in the present invention also comprises the preparation method of the Orally taken pulsed release preparation of development slightly solubility benzodiazepine, because the pharmacological action of this class medicine is strong and effective dose is little, so preparation method must be able to guarantee that medicament contg is accurate, the method favorable reproducibility, for example drug release rate is not subjected to the influence of label pressure etc., cost is low, is fit to suitability for industrialized production.
For solving the problems of the technologies described above, the invention provides following technical scheme:
A kind of pulse sheet for the treatment of early awakening, it contains benzodiazepine chemical compound diazepam, estazolam or triazolam, it is characterized in that: label is made up of benzodiazepine compound and surfactant sodium lauryl sulphate, disintegrating agent, filler basically; Outsourcing pulse clothing layer is made up of acrylic resin polymer, ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer and plasticizer.
The pulse sheet of above-mentioned treatment early awakening, it is characterized in that: in the label, disintegrating agent has carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and/or starch glycol ester sodium, and filler is starch, lactose, microcrystalline Cellulose and/or pregelatinized starch; In the outsourcing pulse clothing layer, the acrylic resin base polymer is enteric solubility II acrylic resin, enteric solubility III acrylic resin, hypromellose phthalate ester and/or hypromellose succinate, and plasticizer is propylene glycol, Polyethylene Glycol, Oleum Ricini, spermol, tween 80, diethyl phthalate and/or triethyl citrate.
The pulse sheet of described treatment early awakening is characterized in that: in the label, and benzodiazepine compound and surfactant sodium lauryl sulphate, disintegrating agent, filler, by weight, ratio is 1: 0.1～0.3: 1.0～5.5: 16～113; In the outsourcing pulse clothing layer, the weight ratio of acrylic resin polymer, ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer and plasticizer is 1: 0.2～0.3: 0.4～1.0.
In addition, the pulse sheet of above-mentioned treatment early awakening can add polyvidone and/or hypromellose as binding agent in the label; Also can add Pulvis Talci, micropowder silica gel and/or magnesium stearate as lubricant.
The pulse sheet of described treatment early awakening is characterized in that by weight: label is a diazepam 1: sodium lauryl sulphate 0.3: lactose and/or pregelatinized starch 12～17: carboxymethyl starch sodium 0.7～1.5; In the outsourcing pulse clothing layer, enteric II acrylic resin 1: ethyl cellulose 0.2～0.3: propylene glycol and/or diethyl phthalate 0.4～0.7.
The pulse sheet of described treatment early awakening is characterized in that by weight: label is an estazolam 1: sodium lauryl sulphate 0.3: microcrystalline Cellulose and/or pregelatinized starch 36～45: carboxymethyl starch sodium 1.0～3.0; In the outsourcing pulse clothing layer, enteric solubility II acrylic resin 1: ethyl cellulose 0.2～0.3: tween 80 and/or triethyl citrate 0.4～0.5.
The pulse sheet of described treatment early awakening is characterized in that by weight: label is a triazolam 1: sodium lauryl sulphate 0.1: starch and/or microcrystalline Cellulose 112-113: cross-linking sodium carboxymethyl cellulose 3.6～5.5; In the outsourcing pulse clothing layer, EudragitS100 1: EudragitRL100 0.2～0.3: Oleum Ricini and/or triethyl citrate 0.5～0.6.
A kind of pulse piece preparation method for the treatment of early awakening is characterized in that:
1) mixes with disintegrating agent, filler with the surfactant sodium lauryl sulphate by benzodiazepine compound, be pressed into label;
2) be scattered in the ethanol by acrylic resin polymer, ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer and plasticizer, form suspension;
3) with suspension 2) to label 1) coating.
Described pulse piece preparation method is characterized in that:
1) preparation of label, behind benzodiazepine compound and surfactant sodium lauryl sulphate dry blending, the disintegrating agent of adding is carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and/or starch glycol ester sodium; The filler that adds is starch, lactose, microcrystalline Cellulose and/or pregelatinized starch; Be pressed into label;
2) preparation of pulse coating suspension, acrylic resin base polymer are enteric solubility II acrylic resin, enteric solubility III acrylic resin, hypromellose phthalate ester and/or hypromellose succinate; Hydrophobicity ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer; Plasticizer is propylene glycol, Polyethylene Glycol, Oleum Ricini, spermol, tween 80, diethyl phthalate and/or triethyl citrate; Be scattered in 95% ethanol.
3) with suspension 2) to label 1) coating.
The preparation method of above-mentioned pulse sheet is characterized in that: in the label, the weight ratio of benzodiazepine compound and surfactant sodium lauryl sulphate, disintegrating agent, filler is 1: 0.2～0.5: 0.5～3.0: 11～43; In the outsourcing pulse clothing layer, acrylic resin polymer, ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer, plasticizer and alcoholic acid by weight/volume are 1: 0.2～0.3: 0.4～1.0: 10.0～20.0.
The preparation method of described pulse sheet is characterized in that: can add an amount of polyvidone and/or hypromellose in the label routinely as binding agent; Also can add an amount of Pulvis Talci, micropowder silica gel and/or magnesium stearate as lubricant; Tabletting after can granulating, the wet grain of a label baking temperature is 50～60 ℃, be 1～3 hour drying time.
The formula I chemical compound that the present invention relates to treat early awakening is a benzodiazepine, such medicine comprises: diazepam, estazolam, triazolam, they not only have common parent nucleus on the chemical constitution, and have some common features aspect physics and chemistry and the pharmaceutical properties, for example, almost insoluble in water, certain solubility is arranged in the stomach, in intestinal, absorb rapidly.The degree of drug absorption is relevant with intestinal pH, and the prominent time and the dissolubility released of medicine arranged so influence the bioavailability principal element.The present invention adds the surfactant sodium lauryl sulphate, to increase the hydrophilic of insoluble drug, prevents the medicine cohesion, increases the dissolution rate of principal agent composition, impels its rapid dissolving.
Label prescription provided by the invention, disintegrating agent mainly contains carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch glycol ester sodium; Filler mainly contains starch, lactose, microcrystalline Cellulose and/or pregelatinized starch etc.Can add binding agent and/or lubricant again, but be not requisite, also can not add binding agent and/or lubricant.Binding agent can adopt polyvidone or hypromellose.Lubricant can be used Pulvis Talci, micropowder silica gel or magnesium stearate etc.
In the invention, the material that is used to wrap film-coat or coatings comprises; The acrylic resin base polymer, as: enteric solubility II acrylic resin (as Eudragit L100), enteric solubility III acrylic resin (as EudragitS100), hypromellose phthalate ester, hypromellose succinate etc., its consumption is 5～8% (w/v).Contain a kind of lyophobic dust in the coating solution, as: ethyl cellulose can be called by commodity in use
Aquacoat@, AsahiKasei or Surelease
@, Colorcon or a kind of methacrylic acid trimethylammonium ethyl ester-acrylate copolymer (as EudragitRL or EudragitRS), its consumption 1.5～2.5% (w/v), the lyophobic dust of Chang Xuan is an ethyl cellulose.Add plasticizer in the film-coat prescription, as: propylene glycol, Polyethylene Glycol, Oleum Ricini, spermol, tween 80, diethyl phthalate and/or triethyl citrate, optimum amount are 2～3% (w/v).
Label of the present invention can adopt the ordinary coating method, and for example, fluidized bed coating or pot rolling coating method can wrap one deck or two layers of clothing.
The present invention relates to pulsatile drug delivery system, especially coating stripping and the oral timed release coating medicinal tablet that combines of burst releasing mechanism.
Benzodiazepine pulse sheet of the present invention is characterised in that, during external dissolution test, a time lag arranged in gastro-intestinal Fluid, when tablet arrives the intestinal certain position, discharge medicine immediately, form pulse blood drug level peak, the not influence of pressure size during the pressurized chip of this drug release rate.
Pulsatile release tablets agent provided by the invention, oral back medicine does not discharge immediately, but lags behind when certain, and medicine discharges from tablet rapidly, and blood drug level presents the pulsed peak value.Its advantage is that patient takes a medicine at bedtime, and can release a certain dose drug at early awakening prolapse at night, plays sedative-hypnotic effect, makes patient be in sleep state once more, has best bioavailability.
Because pulsatile release tablets agent of the present invention is short action time, the hysteresis drug effect of no slow releasing tablet is promptly drowsiness, can not influence second day operate as normal.The present invention can reach the optimum efficiency for the treatment of the early awakening patient with the medicine of minimum dose.In addition, if desired, pulse sheet of the present invention can with the ordinary tablet drug combination, the person that makes difficulty falling asleep safety rapidly is sleeping, and makes the early awakening person is stable and sleep to early morning.
The preparation method of the pharmaceutical dosage form of delayed release provided by the invention proves favorable reproducibility in the implementation process, even pressure changes to some extent during tabletting, also do not influence the drug release rate of pulse preparation of the present invention; The pulse preparation of the inventive method preparation can guarantee that drug dose is accurate; And technology is simple relatively, and production cost is lower, helps suitability for industrialized production.
Description of drawings
Figure: plasma concentration curve (n=6) in diazepam pulse sheet and the common lamellar body
The specific embodiment
Raw material sources and specification:
Diazepam, estazolam (medicinal, changzhou four medicine pharmaceutical Co. Ltds), triazolam (medicinal, grace China Pharmaceutical group, Xuzhou the 3rd pharmaceutical factory), pharmaceutic adjuvant is routine.
Embodiment 1: diazepam pulse sheet
Label prescription: % (W/W)
Diazepam 5.3
Lactose 46.3
Pregelatinized starch 38.8
Carboxymethyl starch sodium 6.5
Sodium lauryl sulphate 1.2
4% polyvidone 1.1
Magnesium stearate 0.8
Preparation technology:
In above-mentioned prescription ratio, diazepam and sodium lauryl sulphate are put in the blender dry blending 8 minutes, with lactose, pregelatinized starch, carboxymethyl starch sodium are put in the blender again, dry blending 12 minutes, binding agent is added in the mixture, make soft material, sieve and make granule of uniform size, put into 55 ℃ of dryings of baking oven 2 hours, add magnesium stearate and mixed 5 minutes, be pressed into label.
Coating prescription: % (W/V)
Enteric solubility II acrylic resin 5.4
Ethyl cellulose 1.6
Propylene glycol 1.0
Diethyl phthalate 2.0
95% ethanol adds to 100.0%
Preparation technology:
In above-mentioned prescription ratio (when the ethanol volume is when milliliter, all the other adjuvants are in gram, down together), several adjuvants are scattered in the even suspended matter of formation in the ethanol earlier, in fluid bed, to 500g diazepam label spray coating, the sheet bed tempertaure is 45 ℃ during the label coating with this suspension, wraps to clothing layer weightening finish to be 4.5% of label weight.
Every pulse sheet contains principal agent 5mg, and once-a-day, usefulness is taken at bed time.
Embodiment 2: diazepam pulse sheet
Label prescription % (W/W)
Diazepam 5.3
Starch 41.6
Microcrystalline Cellulose 44.3
Low-substituted hydroxypropyl cellulose 6.0
Sodium lauryl sulphate 1.2
4% hypromellose 1.1
Micropowder silica gel 0.5
Preparation technology:
In above-mentioned prescription ratio, diazepam and sodium lauryl sulphate are put in the blender dry blending 5 minutes, again with microcrystalline Cellulose, starch, low-substituted hydroxypropyl cellulose are put in the blender, dry blending 15 minutes, binding agent is added in the mixture, make soft material, sieve and make granule of uniform size, put into 53 ℃ of dryings of baking oven 2 hours, add micropowder silica gel and mixed 5 minutes, be pressed into label.
Coating prescription % (W/V)
Hypromellose phthalate ester 6.0
EudragitRL 1.5
Propylene glycol 2.0
Triethyl citrate 3.0
95% ethanol adds to 100.0%
Preparation technology:
In above-mentioned prescription ratio above-mentioned several adjuvants are scattered in earlier in the ethanol and form even thing, in coating pan, to 500g diazepam label spray coating, the sheet bed tempertaure is 40 ℃ and wraps that to increase weight to the clothing layer be 4% during the label coating with this suspension.
Embodiment 3: estazolam pulse sheet
Label prescription % (W/W)
Estazolam 2.1
Microcrystalline Cellulose 47.0
Pregelatinized starch 43.0
Sodium lauryl sulphate 0.5
Carboxymethyl starch sodium 5.8
4% hypromellose 1.2
Micropowder silica gel 0.4
Preparation technology:
In above-mentioned prescription ratio, estazolam and microcrystalline Cellulose, sodium lauryl sulphate are put in the blender, and dry blending 10 minutes is again with pregelatinized starch, carboxymethyl starch sodium is put in the blender, dry blending 10 minutes adds to binding agent in the mixture, makes soft material, sieve and make granule of uniform size, put into 50 ℃ of dryings of baking oven 2.5 hours, and added micropowder silica gel and mixed 5 minutes, be pressed into label.
Coating prescription % (W/V)
Eudragit?L100 8.0
Ethyl cellulose 2.3
Tween 80 1.3
Triethyl citrate 1.7
95% ethanol adds to 100.0%
Preparation technology:
In above-mentioned prescription ratio above-mentioned several adjuvants are scattered in earlier in the ethanol and form even thing, in coating pan, to 500g estazolam label spray coating, the sheet bed tempertaure is 50 ℃ during the label coating with this suspension, wraps that to increase weight to the clothing layer be 3.5%.
Embodiment 4: triazolam pulse sheet
Label prescription % (W/W)
Triazolam 0.83
Starch 50.67
Microcrystalline Cellulose 42.5
Sodium lauryl sulphate 0.1
Cross-linking sodium carboxymethyl cellulose 4.3
4% polyvidone 1.0
Magnesium stearate 0.6
Preparation technology:
In above-mentioned prescription ratio, triazolam and microcrystalline Cellulose, sodium lauryl sulphate are put in the blender, and dry blending 8 minutes is again with starch, cross-linking sodium carboxymethyl cellulose is put in the blender, dry blending 15 minutes adds to binding agent in the mixture, makes soft material, sieve and make granule of uniform size, put into 55 ℃ of dryings of baking oven 2 hours, and added magnesium stearate and mixed 6 minutes, be pressed into label.
Coating prescription % (W/V)
Eudragit?S100 5.8
Eudragit?RL100 1.7
Oleum Ricini 1.8
Triethyl citrate 1.2
95% ethanol adds to 100%
Preparation technology:
In above-mentioned prescription ratio, above-mentioned several adjuvants are scattered in earlier in the ethanol form even thing, in coating pan, to 500g triazolam label spray coating, wrap that to increase weight to the clothing layer be 4.2% with this suspension.
Embodiment 5:
Test instrunment: AGILENT1100 liquid chromatograph, hewlette-packard.
To 6 healthy volunteer's single doses intersection oral diazepam pulse sheets and commercially available ordinary tablet, adopt the reversed-phase HPLC method to measure diazepam concentration in the blood plasma.Method of testing is referring to " Chinese Pharmaceutical Journal " 1996,3 (18): 507 and " Chinese clinical pharmacy magazine " 1999,8 (1): 43～44.
6 healthy volunteers issue diazepam pulse sheet (1 is once, 5mg/ time) at random, commercially available diazepam ordinary tablet (1 is once, 2 * 2.5mg/ time), and one group of per 3 people, intersection is taken medicine, and blood drug level is measured at a plurality of interval points in the back of at every turn taking medicine.Referring to accompanying drawing: plasma concentration curve (n=6) in diazepam pulse sheet and the common lamellar body.
The HPLC data show: the interior blood drug level of patient's body of taking diazepam pulse sheet has an obvious hysteresis peak, be approximately 5～7 hours lag time, has significantly extended release impulse action, as take before sleeping, be applicable to an early awakening patient in morning 3～4, different medicine times before also can sleeping, be applicable to different period early awakening patients by adjusting.
Claims (9)
1, a kind of pulse sheet for the treatment of early awakening, it contains benzodiazepine chemical compound diazepam, estazolam or triazolam, it is characterized in that: by weight, label is made up of with 1: 0.1～0.3: 1.0～5.5: 16～113 ratios benzodiazepine compound and surfactant sodium lauryl sulphate, disintegrating agent, filler basically; Outsourcing pulse clothing layer is made up of with 1: 0.2～0.3: 0.4～1.0 ratios acrylic resin polymer, ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer and plasticizer, and plasticizer is selected from propylene glycol, Polyethylene Glycol, Oleum Ricini, spermol, tween 80, diethyl phthalate and/or triethyl citrate; Outsourcing pulse clothing layer weight is the 3.5-4.5% of plate core weight.
2, according to the pulse sheet of the described treatment early awakening of claim 1, it is characterized in that: in the label, disintegrating agent is carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and/or starch glycol ester sodium, and filler is starch, lactose, microcrystalline Cellulose and/or pregelatinized starch; In the outsourcing pulse clothing layer, the acrylic resin base polymer is enteric solubility II acrylic resin, enteric solubility III acrylic resin, hypromellose phthalate ester and/or hypromellose succinate.
3, according to the pulse sheet of claim 1 treatment early awakening, can add polyvidone and/or hypromellose in the label as binding agent; Also can add Pulvis Talci, micropowder silica gel and/or magnesium stearate as lubricant.
4, according to the pulse sheet of the described treatment early awakening of one of claim 1 to 3, it is characterized in that by weight: label is a diazepam 1: sodium lauryl sulphate 0.3: lactose and/or pregelatinized starch 12～17: carboxymethyl starch sodium 1.0～1.5; In the outsourcing pulse clothing layer, enteric solubility II acrylic resin 1: ethyl cellulose 0.2～0.3: propylene glycol and/or diethyl phthalate 0.4～0.7.
5, according to the pulse sheet of the described treatment early awakening of one of claim 1 to 3, it is characterized in that by weight: label is an estazolam 1: sodium lauryl sulphate 0.3: microcrystalline Cellulose and/or pregelatinized starch 36～45: carboxymethyl starch sodium 1.0～3.0; In the outsourcing pulse clothing layer, enteric solubility II acrylic resin 1: ethyl cellulose 0.2～0.3: tween 80 and/or triethyl citrate 0.4～0.5.
6, according to the pulse sheet of the described treatment early awakening of one of claim 1 to 3, it is characterized in that by weight: label is a triazolam 1: sodium lauryl sulphate 0.1: starch and/or microcrystalline Cellulose 112-113: cross-linking sodium carboxymethyl cellulose 3.6～5.5; In the outsourcing pulse clothing layer, enteric solubility III acrylic resin 1: methacrylic acid trimethylammonium ethyl ester-acrylate copolymer 0.2～0.3: Oleum Ricini and/or triethyl citrate 0.5～0.6.
7, a kind of pulse piece preparation method for the treatment of early awakening is characterized in that:
1) mixes by 1: 0.1～0.3: 1.0～5.5: 16～113 weight ratios with disintegrating agent, filler with the surfactant sodium lauryl sulphate by benzodiazepine compound, be pressed into label;
2) be scattered in the ethanol by acrylic resin polymer, ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer and plasticizer, form suspension, acrylic resin polymer, ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer, plasticizer and 95% alcoholic acid by weight/volume are 1: 0.2～0.3: 0.4～1.0: 10.0～20.0, and plasticizer is selected from propylene glycol, Polyethylene Glycol, Oleum Ricini, spermol, tween 80, diethyl phthalate and/or triethyl citrate;
3) with suspension 2) to label 1) coating in fluid bed or coating pan, wrap to the weightening finish of clothing layer and be the 3.5-4.5% of label weight.
8, according to the described pulse piece preparation method of claim 7, it is characterized in that:
1) preparation of label, behind benzodiazepine compound and surfactant sodium lauryl sulphate dry blending, the disintegrating agent of adding is carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and/or starch glycol ester sodium; The filler that adds is starch, lactose, microcrystalline Cellulose and/or pregelatinized starch; Be pressed into label;
2) preparation of pulse coating suspension, acrylic resin base polymer are enteric solubility II acrylic resin, enteric solubility III acrylic resin, hypromellose phthalate ester and/or hypromellose succinate; Ethyl cellulose or methacrylic acid trimethylammonium ethyl ester-acrylate copolymer; Plasticizer is propylene glycol, Polyethylene Glycol, Oleum Ricini, spermol, tween 80, diethyl phthalate and/or triethyl citrate; Be scattered in 95% ethanol,
3) with suspension 2) to label 1) coating.
9, the preparation method of described according to Claim 8 pulse sheet is characterized in that: add an amount of polyvidone and/or hypromellose in the label routinely as binding agent; Also can add an amount of Pulvis Talci, micropowder silica gel and/or magnesium stearate as lubricant; Tabletting after can granulating, the wet grain of a label baking temperature is 50～60 ℃, be 1～3 hour drying time.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02137935 CN1188131C (en) | 2002-07-11 | 2002-07-11 | Orally taken pulsed releasing system of phenyl diazepine medicine and its prepn. |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02137935 CN1188131C (en) | 2002-07-11 | 2002-07-11 | Orally taken pulsed releasing system of phenyl diazepine medicine and its prepn. |
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| CN1188131C true CN1188131C (en) | 2005-02-09 |
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| CN100540135C (en) * | 2007-07-06 | 2009-09-16 | 华南师范大学 | The preparation method of benzene phenodiazine quasi-molecule surface print solid-phase extractant |
| CN102974322B (en) * | 2012-10-31 | 2014-12-03 | 浙江工业大学 | Hydrophobic silica gel composite resin-based VOC adsorbent |
| CN103768607B (en) * | 2014-02-19 | 2015-07-15 | 东南大学 | Self-assembled multi-pulse drug-release device, and preparation method and application thereof |
| CN114366720B (en) * | 2021-12-11 | 2023-07-21 | 江苏恩华药业股份有限公司 | Abuse-proof triazolam oral tablet and preparation method thereof |
| CN114848650B (en) * | 2022-05-10 | 2023-10-31 | 南京唯创远医药科技有限公司 | Stable esmolol formulation composition and preparation method thereof |
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