CN1810237A - Slow-released ambroxol salt tablet and its prepn process - Google Patents
Slow-released ambroxol salt tablet and its prepn process Download PDFInfo
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- CN1810237A CN1810237A CN 200510013162 CN200510013162A CN1810237A CN 1810237 A CN1810237 A CN 1810237A CN 200510013162 CN200510013162 CN 200510013162 CN 200510013162 A CN200510013162 A CN 200510013162A CN 1810237 A CN1810237 A CN 1810237A
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Abstract
The slow-released ambroxol salt tablet consists of ambroxol salt 10-60 wt%, retarder 10-50 wt%, and medicinal supplementary material. It has specific extracorporeal releasing degree in water, buffering liquid or simulated physiological environment. The slow-released ambroxol salt tablet has simple production apparatus, easy control of the medicine releasing speed, less influence of physiological factors, pH value, movement, etc of intestinal tract on the medicine releasing speed, less disintegrating possibility, taking safety, less toxic side effect and high bioavailability, and can meet the requirement of different types of patients.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically, is a kind of slow-released ambroxol salt tablet and manufacture method thereof.
Background technology
The ambroxol hydrochloride chemistry is by name: methyl-amino trans 4-[(2-amino-3,5 two bromo-phenyl)] the Hexalin hydrochlorate.Its preparation method is referring to GB1991, and 2239242.
(ambroxol hydrochloride Amb) is the active metabolite of bromhexine to ambroxol hydrochloride, is a kind of new mucolytic drugs, can promote bronchus cilium emptying campaign, helps airway secretions and discharges.Its toxicity is low, eliminates the phlegm and to improve the pulmonary function effect strong, and be one of the most frequently used expelling phlegm drugs.
Commercially available ambroxol sheet need be taken medicine 3 every day.Be to improve patient's compliance, open and upright superfinely adopt piller film control techniques to prepare the ambroxol hydrochloride sustained-release capsule " The 2nd Army Medical College journal " 2000 the 21st volume the 4th interim mentioning.Fenestra piller slow releasing capsule has release concordance preferably, in the advantages such as influence of the gastrointestinal absorption unable to take food thing rhythm and pace of moving things, but owing to the film control techniques will be finished by multiple coatings, so manufacturing cycle is longer, and production efficiency is difficult to improve, and cost is higher.
The third-class people of Pan Wei 2003 Chinese patent (publication number CN1415287) provided the method for preparing the ambroxol osmotic pump type controlled release preparation, comprise label in the method for making, three ingredients of coating membrane and drug release hole are utilized the release of osmotic pressure principle control medicine.Contain the hyperosmosis material in the label, label outsourcing control speed semipermeable membrane, open one or more small delivery aperture with laser on the film, oral back gastrointestinal moisture enters label by semipermeable membrane, make medicine be dissolved into saturated solution or suspension, sheet in-core height oozes the dissolving of material in addition, forms hyperosmotic solution in the tablet film.Under the promotion of permeable pressure head big inside and outside the film, drug solution continues to pump by small delivery aperture.The size in the thickness of coating membrane, permeability and drug release hole aperture is the key problem in technology of drug release rate, and the coating permeability of the membrane is big, and moisture enters in the film fast, and then drug release rate is fast.The aperture of small delivery aperture is little, will reduce drug release rate, and the aperture greatly then produces too high release result, so the size of small delivery aperture must be suitable, just can obtain ideal rate of releasing drug.It is bigger that the thickness of coating membrane also disengages influence to medicine, and lepthymenia then fastness is not enough, in case break, medicine will come down in torrents to produce to collapse and release, and cause the danger of overdose, and film is blocked up, and rate of releasing drug is slow excessively, then is difficult to guarantee the blood concentration of continuous and effective.Therefore it is more that osmotic pump type controlled release preparation production needs the link of strict control, to having relatively high expectations of Producer and working condition, generally needs to adopt special equipment, and cost is higher.
Liu Guoliangs etc. are that basic framework prepares ambroxol hydrochloride sustained-release tablet at 2004 " Shenyang Pharmaceutical University's journal " the 21st volume the 2nd interim Rikemal B 200 of mentioning with bioerodible (Compritol 888 ATO), be good inside and outside dependency on one's body domesticated dog, with the ambroxol hydrochloride sustained-release capsule bioequivalence that has gone on the market.The release of bioerodible sustained-release matrix tablets Chinese medicine is because the solid Ester is digested hydrolysis and corrosion gradually in the physiological environment in vivo gradually, the pH of some physiologic factors such as Digestive system, digestive enzyme etc. can influence the speed of the hydrolysis corrosion of esters largely, thereby medicine also can be subjected to the influence of these physiologic factors from the speed that wherein discharges.
Shortcomings and deficiencies in various degree in view of above-mentioned existing dosage form existence, the object of the present invention is to provide a kind of manufacturing process simple relatively, do not need complex device promptly can make, drug release is easy to control, the rate of release of medicine is changed by gastrointestinal physiologic factor, pH value and peristaltic velocity etc. influences lessly, and it is little to collapse the probability of releasing, and takes safety, toxic and side effects is little, slow-released ambroxol salt tablet agent that bioavailability is high and preparation method thereof.
Summary of the invention
Slow-released ambroxol salt tablet of the present invention, be made up of by weight percentage following composition: ambroxol salt 10%～60%, blocker are 10%～50%, all the other adjunct ingredients are surplus.Be preferably ambroxol salt 20%～60%, blocker is 10%～40%, and all the other pharmaceutic adjuvant compositions are surplus, preferred ambroxol salt 30%～50%, and blocker is 15%～30%, all the other pharmaceutic adjuvant compositions are surplus.
Ambroxol pharmaceutical salts of the present invention is the acceptable salt of physiology, can be inorganic salt, example hydrochloric acid salt, and sulfate etc. also can be organic salt, as maleate or mesylate etc.Preferred salt hydrochlorate or mesylate.
Blocker of the present invention can be a cellulose derivative: as ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., and inertia waxiness, fatty acid and Ester thereof: as stearic acid, glyceryl monostearate, octadecanol etc.Other has the material that delays the drug release effect, can also be polyethylene, polypropylene, polysiloxanes, acrylic resin etc.
Porogen, binding agent and lubricant that all the other pharmaceutic adjuvants of the present invention can be the scalable drug release rates.Wherein porogen is that saccharide, electrolyte or other have the material of governing speed effect.Glucide is lactose, sucrose, fructose, sorbitol or mannitol etc.; The electrolytes material is sodium chloride, potassium chloride etc.; The material of other scalable drug release rate is: Polyethylene Glycol series is as Macrogol 4000, polyethylene glycol 6000, polyvinylpyrrolidone, microcrystalline Cellulose and water soluble surfactant active etc.
All the other adjuvants of the present invention also comprise binding agent, lubricant.As lactose, sucrose, starch, cellulose or the like; Wherein binding agent is mixed solution, polyvinylpyrrolidone, the dry powder of cellulose derivative or the mixed solution of its water alcohol etc. of water or alcohol or water and alcohol; Lubricant is magnesium stearate (or calcium), Pulvis Talci, micropowder silica gel, sodium lauryl sulphate or magnesium or the like.
The preparation method of slow-released ambroxol salt tablet of the present invention comprises: will directly be pressed into tablet by powder behind the supplementary material mixing; Or make tablet with lubricant mixing repress after making granule; Or get part material and auxiliary materials and mixing earlier, and make immediate release section, the raw material of surplus and blocker mixing as slow-released part, are pressed into the bilayer or the multilayer tablet that have release layer and slow release layer simultaneously.
Characteristics of the present invention are to contain in the prescription matrix type retardance material.The retardance material can be also can be to stable insoluble retardance materials such as the moisture in the Digestive system, acid, alkali, enzymes by the retardance material of the moisture in the Digestive system, acid, alkali, enzyme corrosion.Retardance material preferred hydrophilic gel type (water erosion type) framework material such as hydroxypropyl emthylcellulose etc. and insoluble ethyl cellulose etc.The mixing of supplementary material can be dry powder blend such as ambroxol salt, blocker, filler, also can be after mixing, to make medicine-containing particle under the moistening of alcohol-water solution, and oven dry is sieved at a certain temperature, is pressed into tablet with the lubricant mixing then.Adopt conventional tablet equipment to produce, production cost is lower, and technology is simpler, is easy to suitability for industrialized production.
The slow-released ambroxol salt tablet agent that makes according to manufacture method of the present invention, the drug release characteristics that has in water, pH6.8 and 7.4 buffer (press Chinese Pharmacopoeia method preparation) or mimic physiological environment (in the simulated gastric fluid 1～2 hour, change simulated intestinal fluid again over to) is:
Time (h) accumulative total discharges %
1 15％～45％
2 25％～75％
4 40％～95％
8 55％～100％
12 70％～100％
24 85％～100％。
Be raw material for example with the ambroxol salt hydrochlorate, a kind of ambroxol hydrochloride sustained-release tablet that makes by manufacture method of the present invention, drug release characteristics in water, pH6.8 and 7.4 buffer (press Chinese Pharmacopoeia method preparation) or mimic physiological environment (in the simulated gastric fluid 1～2 hour, change simulated intestinal fluid again over to) is:
Time (h) accumulative total discharges %
1 25.3％
2 45.9％
4 66.7％
8 78.6％
12 87.1％
24 97.0％。
According to the slow-released ambroxol salt tablet agent that manufacture method of the present invention makes, Digestive system is met in oral back in gastrointestinal tract, at first form block layer in the tablet surface moistening, and the top layer medicine spreads in Digestive system rapidly; Block layer continues aquation, the skeleton swelling, and block layer thickens and delays drug release; The corrosion simultaneously of tablet skeleton, moisture infiltrates into the complete corrosion of skeleton to label, and medicine all discharges.Slow down gradually owing to the block layer progressive additive makes rate of releasing drug, thereby the release of medicine shows as characteristics first quick and back slow, this is useful to clinical use, and medicine a large amount of strippings in oral rear surface make blood drug level reach the treatment desired concn rapidly, the performance drug effect.Then block layer thickens drug slow is discharged, to keep treatment concentration.Because skeleton retardance material is mainly the erodible material of water, thereby the rate of release of medicine is subjected to the gastrointestinal physiologic factor, pH value change and influence such as peristaltic velocity less, thereby difference is less between sheet, stable curative effect.To collapse the probability of releasing minimum because of such slow releasing tablet, so the safety of taking.
Test in the domesticated dog body according to the ambroxol hydrochloride sustained-release tablet that manufacture method of the present invention makes, absorption has significant dependency in its release in vitro degree and the domesticated dog body, and correlation coefficient is 0.974.With commercially available ambroxol hydrochloride sustained-release capsule is reference, measure the intravital blood drug level of domesticated dog, this slow releasing tablet to the relative bioavailability of reference preparation at 80～125%, peak concentration and reference preparation ratio are at 70～145%, with the reference preparation bioequivalence, and manufacturing cost and to the requirement of working condition than reducing greatly, thereby reduced patient's medical expense.
Manufacture method of the present invention, do not need complex device promptly can make, drug release is easy to control, the rate of release of medicine is subjected to the gastrointestinal physiologic factor, pH value change and influence such as peristaltic velocity less, it is little to collapse the probability of releasing, take safety, toxic and side effects is little, and the bioavailability height can satisfy requirement of different patients.
The specific embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only means never that for indicative it limits the scope of the invention by any way.
Embodiment 1:
Ambroxol salt hydrochlorate 75.0g
Lactose 30.0g
Microcrystalline Cellulose 5.0g
Hydroxypropyl emthylcellulose 25.0g
Polyethylene glycol 6000 4.0g
Magnesium stearate q.s
Pulvis Talci q.s
Micropowder silica gel q.s
80% ethanol q.s
Embodiment 2:
Ambroxol salt hydrochlorate 75.0g
Lactose 85.0g
Hydroxypropyl emthylcellulose 80.0g
Calcium hydrogen phosphate 10.0g
Magnesium stearate q.s
Micropowder silica gel q.s
Ethanol q.s
Embodiment 3:
Ambroxol mesylate 86.0g
Lactose 180.0g
Microcrystalline Cellulose 55.0g
Hydroxypropyl emthylcellulose 80.0g
Ethyl cellulose 45.0g
Polyethylene glycol 6000 10.0g
Sodium chloride 20.0g
Magnesium stearate q.s
Pulvis Talci q.s
Micropowder silica gel q.s
Preparation technology operates as follows:
1. the supplementary material crushing screening is got ambroxol salt and other adjuvants, directly or behind dry granulation suppresses in flakes behind the mixing.
2. the supplementary material crushing screening is got ambroxol salt and other adjuvants, makes wetting agent system granule with adequate amount of ethanol, and lubricant mixings such as dry back and magnesium stearate are pressed into tablet.
3. get 5%～20% of ambroxol salt recipe quantity, with auxiliary materials and mixing such as lactose, as immediate release section; Auxiliary materials and mixing such as the ambroxol salt of surplus and hydroxypropyl emthylcellulose, ethyl cellulose as slow-released part, are pressed into the bilayer or the multilayer tablet that have release layer and slow release layer simultaneously.
Claims (7)
1, a kind of slow-released ambroxol salt tablet, be made up of by weight percentage following composition: ambroxol salt 10%～60%, blocker are 10%～50%, the pharmaceutic adjuvant composition is a surplus.
2, slow-released ambroxol salt tablet according to claim 1, wherein said ambroxol salt can be physiologically acceptable salts.
3, slow-released ambroxol salt tablet according to claim 1, wherein said blocker are that cellulose derivative, inertia waxiness, fatty acid and Ester thereof or other have the material that delays the drug release effect.
4, slow-released ambroxol salt tablet according to claim 1, wherein said pharmaceutic adjuvant is: porogen, binding agent, lubricant.
5, according to the described slow-released ambroxol salt tablet of a tree name claim 4, wherein said porogen is that saccharide, electrolyte or other have the material of governing speed effect.
6, a kind of preparation method of slow-released ambroxol salt tablet is characterized in that: will directly be pressed into tablet by powder behind the supplementary material mixing; Or make tablet with lubricant mixing repress after making granule; Or get part material and auxiliary materials and mixing earlier, and make immediate release section, the raw material of surplus and blocker mixing as slow-released part, are pressed into the bilayer or the multilayer tablet that have release layer and slow release layer simultaneously.
7, a kind of slow-released ambroxol salt tablet, the drug release characteristics that this slow releasing tablet has in water, pH6.8 and 7.4 buffer or mimic physiological environment is:
Time (h) accumulative total discharges %
1 15％～45％
2 25％～75％
4 40％～95％
8 55％～100％
12 70％～100％
24 85％～100％。
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|---|---|---|---|
| CN 200510013162 CN1810237A (en) | 2005-01-28 | 2005-01-28 | Slow-released ambroxol salt tablet and its prepn process |
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| CN 200510013162 CN1810237A (en) | 2005-01-28 | 2005-01-28 | Slow-released ambroxol salt tablet and its prepn process |
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| CN1810237A true CN1810237A (en) | 2006-08-02 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105828808A (en) * | 2013-12-26 | 2016-08-03 | 现代药品株式会社 | Sustained-release pharmaceutical composition containing acebrophylline and hydrophobic sustained-release agent |
| CN105916494A (en) * | 2013-12-26 | 2016-08-31 | 现代药品株式会社 | Sustained-release pharmaceutical composition containing acebrophylline and hydrophillic sustained-release agent |
| CN111135152A (en) * | 2020-01-19 | 2020-05-12 | 安徽省先锋制药有限公司 | Preparation method of ambroxol hydrochloride capsule |
-
2005
- 2005-01-28 CN CN 200510013162 patent/CN1810237A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105828808A (en) * | 2013-12-26 | 2016-08-03 | 现代药品株式会社 | Sustained-release pharmaceutical composition containing acebrophylline and hydrophobic sustained-release agent |
| CN105916494A (en) * | 2013-12-26 | 2016-08-31 | 现代药品株式会社 | Sustained-release pharmaceutical composition containing acebrophylline and hydrophillic sustained-release agent |
| CN105828808B (en) * | 2013-12-26 | 2020-03-13 | 现代药品株式会社 | Sustained-release pharmaceutical composition containing acebrophylline and hydrophobic sustained-release agent |
| CN111135152A (en) * | 2020-01-19 | 2020-05-12 | 安徽省先锋制药有限公司 | Preparation method of ambroxol hydrochloride capsule |
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Open date: 20060802 |