CN102641252A - Terbinafine hydrochloride solid dispersoid and tablet thereof - Google Patents
Terbinafine hydrochloride solid dispersoid and tablet thereof Download PDFInfo
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- CN102641252A CN102641252A CN2012101391925A CN201210139192A CN102641252A CN 102641252 A CN102641252 A CN 102641252A CN 2012101391925 A CN2012101391925 A CN 2012101391925A CN 201210139192 A CN201210139192 A CN 201210139192A CN 102641252 A CN102641252 A CN 102641252A
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- terbinafine hcl
- terbinafine hydrochloride
- terbinafine
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Abstract
The invention relates to a terbinafine hydrochloride solid dispersoid, which is composed of terbinafine hydrochloride and carrier materials, wherein the proportion by weight between the terbinafine hydrochloride and the carrier materials is 1/2-1/15. The invention further relates to a tablet prepared by the terbinafine hydrochloride solid dispersoid. Compared with the prior art, the terbinafine hydrochloride tablet has the advantages of (1) improving dissolution in vitro of terbinafine hydrochloride preparation; (2) solving the problem that the terbinafine hydrochloride is poor in oral administration absorption and low in biological availability; (3) covering harmful odor and irritation of the terbinafine hydrochloride; (4) keeping pesticide effects of large dose while reducing using quantity of active ingredients in the preparation per unit, and reducing drug side-effects; and (5) being simple in preparation process and suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of terbinafine HCl solid dispersion and tablet thereof.
Background technology
Show that according to social epidemiology's investigation fungal infection is a sickness rate disease with high, and have again the high characteristics of infection rate.In China, the sickness rate of fungal infection has reached 78%, thereby has promoted the rapid growth in antifungal drug market.According to Chinese Medicine industrial information central database data show, in the period of 2006～2010, domestic 22 city sample hospital antifungal medicine market annual rate of growth are all more than 20%, and soaring year by year; 2010; Domestic 22 city sample hospital anti-fungal infection medicine overall market shares have reached 12.85 hundred million yuan; 9.64 hundred million in 2009 yuan have increased by 33.3% on year-on-year basis; Estimate that present domestic anti-fungal infection medicine overall market scale has reached more than 50 hundred million yuan, wherein the deep fungal infection medicine occupies the market more than 60% always.
Terbinafine HCl (Terbinafine Hydrochloride) is a propylene amine broad-spectrum antifungal medicine; Can disturb the early stage biosynthesis of mycosterol specifically; The activity that optionally suppresses fungus Squalene Cycloxygenase; Squalene epoxidation reaction in the fungal cell membrane forming process is obstructed, thereby reaches the effect of killing or suppressing fungus.Its indication comprises: the infection of skin, hair and first that (1) is caused by trichophyton (trichophyton, alpha fungus, Trichophyton verrucosum, trichophyton tonsurans and Trichophyton violaceum etc.), Sabouraudites lanosus and acrothesium floccosum etc.(2) various tinea (tinea corporis, tinea cruris, tinea manus and pedis and tinea capitis etc.) and the skin yeast infection that causes by candidiasis (Candida albicans etc.).(3) by mouldy microbial tinea unguium (fungal infection of nail).
The chemistry of terbinafine HCl is by name: (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt, be white or off-white color crystalline powder, little have the spy smelly, in ethanol, be prone to dissolve, slightly soluble in water, almost insoluble in ether.Its chemical structural formula is:
Terbinafine HCl absorbs fast in vivo and absorbs good (70%), about 2 hours of peak time, and distribution phase plasma half-life is about 1.1 hours, eliminates the phase plasma half-life and is about 1.5 hours.Mainly metabolism in liver of terbinafine HCl is through n-demethyl or n-hydrogenation and aliphatic hydrocarbon is side-chain hydrogenated or metabolism posthydrolysis such as aromatic hydrocarbons hydride formation becomes dihydrodiol structure metabolite to drain.During the local topical medicine, blood Chinese medicine concentration is very low, and 5% of not enough dosage only can detect with high performance liquid chromatograph.
In order to reach therapeutic effect, contain active component 250mg in the per unit preparation in the existing terbinafine HCl tablet, because drug dose is big, cause said preparation to have some side effect.Modal have gastrointestinal symptom (sensation of fullness, inappetence, feel sick, slightly suffer from abdominal pain and suffer from diarrhoea) or a light-duty dermoreaction (erythra, urticaria etc.); Indivedual serious dermoreaction cases (, toxic epidermal necrolysis comprehensive like Stevens-Johnson) were once appeared in the newspapers; If carrying out property erythra is then answered drug withdrawal; The rare sense of taste changes, and comprises ageusia, and the latter can recover in several weeks after drug withdrawal.Extremely indivedual case generation hepato-biliary functions are incomplete.
In addition, terbinafine HCl is as a kind of insoluble chemical compound, and the dissolution that is made into behind the oral solid formulation in vivo is limited, has influenced its absorption and utilization.Patent documentation CN101548958A discloses a kind of dispersible tablet that contains terbinafine HCl; Through terbinafine HCl active component and filler, binding agent, disintegrating agent, lubricant and correctives are mixed and made into dispersible tablet; Improved the dissolution of active component, yet the active component absorption in vivo is undesirable behind the oral said preparation.
This shows, research and develop out that a kind of stripping is fast, good absorbing, safe terbinafine HCl solid orally ingestible seem particularly urgent.
Summary of the invention
The present invention has overcome deficiency of the prior art, provides that a kind of stripping is fast, good absorbing, safe terbinafine HCl solid dispersion and tablet thereof.
Concrete technical scheme of the present invention is following:
A kind of terbinafine HCl solid dispersion is made up of terbinafine HCl and carrier material, and wherein, the weight ratio of terbinafine HCl and carrier material is 1:2～1:15.
As improvement, the weight ratio of terbinafine HCl and carrier material is 1:5～1:10.
Described carrier material is selected from a kind of in polyoxyethylene (40) stearate or the poloxamer.
The invention still further relates to the tablet that adopts above-mentioned terbinafine HCl solid dispersion to process, it is counted by weight and includes following material:
Terbinafine HCl solid dispersion 241～360
Microcrystalline Cellulose 82～93
Carboxymethyl starch sodium 8～12
Colloidal silica 2～3
Magnesium stearate 4～4.5.
Compared with prior art, the terbinafine HCl tablet that the present invention relates to has following advantage: the dissolution in vitro of terbinafine HCl preparation has been improved in (1); (2) improved the deficiency that the terbinafine HCl oral absorption is poor, bioavailability is low; (3) cover the bad smell and the zest of terbinafine HCl; Keep strong dose to imitate when (4) reducing in the per unit preparation active component consumption, reduced drug side effect; (5) preparation technology is simple, is fit to industrialization production.
Description of drawings
Curve when Fig. 1 is the medicine behind the oral 240mg terbinafine HCl of the human body sheet.
The specific embodiment
Below in conjunction with the specific embodiment of terbinafine HCl solid dispersion and tablet thereof, technical scheme of the present invention is further described, but protection scope of the present invention is not limited to these embodiment.Every do not deviate from the present invention design or the present invention done to be equal to substitute include within protection scope of the present invention.
Embodiment 1
The preparation of terbinafine HCl solid dispersion
Get 50g poloxamer 188 and put into appropriate vessel, place 65 ℃ of-68 ℃ of water-baths to be heated to fused liquid state, add 10g terbinafine HCl fine powder; Be stirred to mix homogeneously fast in 63 ℃-66 ℃, leave standstill and remove bubble, mixture is spread out straticulation and puts into-5 ℃ of refrigerators cool off fast; Take out after the thing full solidification to be mixed, pulverize; And place 35 ℃ of dry 24h of vacuum desiccator, and pulverized 80 mesh sieves, promptly get the terbinafine HCl solid dispersion.
Embodiment 2
The preparation of terbinafine HCl solid dispersion
Getting the 10g terbinafine HCl, to join in the 200mL water-ethanol ultrasonic dissolution subsequent use; Getting 150g polyoxyethylene (40) stearate is heated to 60 ℃-62 ℃ and makes it to fused liquid state; Stir the terbinafine HCl alcoholic solution that adding down prepares fast, volatilize solvent, putting into-5 ℃ of refrigerators cools off fast; Pulverize 80 mesh sieves, promptly got the terbinafine HCl solid dispersion.
Embodiment 3
The preparation of terbinafine HCl solid dispersion
Get 20g poloxamer 188 and put into appropriate vessel, place 65 ℃ of-68 ℃ of water-baths to be heated to fused liquid state, add 10g terbinafine HCl fine powder; Be stirred to mix homogeneously fast in 63 ℃-66 ℃, leave standstill and remove bubble, mixture is spread out straticulation and puts into-5 ℃ of refrigerators cool off fast; Take out after the thing full solidification to be mixed and pulverize; 35 ℃ of dry 24h pulverized 80 mesh sieves in vacuum desiccator, promptly got the terbinafine HCl solid dispersion.
Embodiment 4
The preparation of terbinafine HCl solid dispersion
Get 80g poloxamer 188 and put into appropriate vessel, place 65 ℃ of-68 ℃ of water-baths to be heated to fused liquid state, add 10g terbinafine HCl fine powder; Be stirred to mix homogeneously fast in 63 ℃-66 ℃, leave standstill and remove bubble, mixture is spread out straticulation and puts into-5 ℃ of refrigerators cool off fast; Take out after the thing full solidification to be mixed and pulverize; And put 35 ℃ of dry 24h in the vacuum desiccator, and pulverized 80 mesh sieves, promptly get the terbinafine HCl solid dispersion.
Embodiment 5
The preparation of terbinafine HCl solid dispersion
Getting the 10g terbinafine HCl, to join in the 200mL water-ethanol ultrasonic dissolution subsequent use; Getting 100g polyoxyethylene (40) stearate is heated to 60 ℃-62 ℃ and makes it to fused liquid state; Stir the terbinafine HCl alcoholic solution that adding down prepares fast, volatilize solvent, putting into-5 ℃ of refrigerators cools off fast; Pulverize 80 mesh sieves, promptly got the terbinafine HCl solid dispersion.
Embodiment 6
The preparation of terbinafine HCl solid dispersion
Getting the 10g terbinafine HCl, to join in the 200mL water-ethanol ultrasonic dissolution subsequent use; Getting 80g polyoxyethylene (40) stearate is heated to 60 ℃-62 ℃ and makes it to fused liquid state; Stir the terbinafine HCl alcoholic solution that adding down prepares fast, volatilize solvent, putting into-5 ℃ of refrigerators cools off fast; Pulverize 80 mesh sieves, promptly got the terbinafine HCl solid dispersion.
Embodiment 7
The preparation of terbinafine HCl tablet
Prescription is formed:
Preparation technology: get terbinafine HCl solid dispersion 241 g that embodiment 1 prepares and microcrystalline Cellulose, the carboxymethyl starch sodium mix homogeneously in the above-mentioned prescription; Described getting; Add colloidal silica, magnesium stearate mix homogeneously; Press 1000, the every about 41mg of hydrochloric terbinafine.
Embodiment 8
The preparation of terbinafine HCl tablet
Prescription is formed:
Preparation technology: get terbinafine HCl solid dispersion 352 g that embodiment 3 prepares and microcrystalline Cellulose, the carboxymethyl starch sodium mix homogeneously in the above-mentioned prescription; Add colloidal silica, magnesium stearate mix homogeneously; Press 1000, the every about 120mg of hydrochloric terbinafine.
Embodiment 9
The preparation of terbinafine HCl tablet
Prescription is formed:
Preparation technology: get terbinafine HCl solid dispersion 360 g that embodiment 6 prepares and microcrystalline Cellulose, the carboxymethyl starch sodium mix homogeneously in the above-mentioned prescription; Add colloidal silica, magnesium stearate mix homogeneously; Press 1000, the every about 43mg of hydrochloric terbinafine.
Comparative Examples 1
The preparation of terbinafine HCl dispersible tablet
Prescription is formed:
Preparation technology: get terbinafine HCl and lactose, mannitol, microcrystalline Cellulose, the cross-linking sodium carboxymethyl cellulose of above-mentioned recipe quantity, mix homogeneously, the system soft material is crossed 20 mesh sieves and is granulated drying, 24 mesh sieve granulate; Add the magnesium stearate and the citric acid mix homogeneously of recipe quantity, press 1000, the every about 120mg of hydrochloric terbinafine.
Comparative Examples 2
The preparation of terbinafine HCl sheet
Preparation technology: the terbinafine HCl raw material pulverizing is crossed 120 mesh sieves; From siftage, get terbinafine HCl fine powder and microcrystalline Cellulose, the carboxymethyl starch sodium mix homogeneously of recipe quantity; Add colloidal silica, magnesium stearate mix homogeneously; Press 1000, the every about 120mg of hydrochloric terbinafine.
The dissolution determination test of terbinafine HCl sheet
Sample thief is measured according to dissolution method (2010 editions two appendix X C of Chinese Pharmacopoeia, second method), is solvent with purified water 900mL; Rotating speed is that per minute 75 changes, and operation in accordance with the law is in the time of 30 minutes; It is an amount of to get solution, filters with 0.45 μ m filter membrane, gets the subsequent filtrate need testing solution; It is an amount of that precision takes by weighing the terbinafine HCl reference substance in addition, adds methanol and make its dissolving and dilution process the solution that contains 20 μ g in every 1mL methanol in right amount, as reference substance solution.Get above-mentioned two kinds of solution, according to 2010 editions (appendix IV A) ultraviolet visible spectrophotometry of Chinese Pharmacopoeia, measure absorbance at the 283nm place, calculate every stripping quantity by external standard method, ask the meansigma methods of each group, the result sees table 1.
Result of the test by table 1 can find out that the dissolution in vitro of terbinafine HCl tablet of the present invention and comparative example 1 do not have king-sized difference, but significantly is superior to the tablet of comparative example's 2 preparations.
Absorption measurement test in the body of terbinafine HCl sheet
12 healthy male volunteers, 20～25 years old age.The experimenter proves that through biochemical investigation liver, renal function are all normal.Experiment the last fortnight to whole experiment is not obeyed any other medicine, experimental session ban on opium-smoking and the opium trade wine.Adopt the design of single dose binary cycle cross-over experiment, after 12 volunteer's random packet, one group of terbinafine HCl tablet of taking the embodiment of the invention 8 preparations, another group is taken the terbinafine HCl tablet of Comparative Examples 1 preparation, and the cleaning phase is 7d, intersects administration then.The healthy volunteer is 12h on an empty stomach, reinstates 200mL warm water delivery service 240mg terbinafine HCl morning.The blood sampling time point is 0,0.5,1,2,3,4,5,6,8,12,24h, ulnar vein blood sampling 3～4mL, centrifugal 10min (5000rmin
-1), blood plasma is put-20 ℃ of freezer storages.
Chromatographic condition chromatographic column: Symmetry C18 (150mm * 4.6mm, 5 μ m); Mobile phase: methanol: water: 5% sodium hydroxide-4-ethylamine (597.4:400:2.6); Detect wavelength: 283 nm; Flow velocity: 1mLmin
-1
Press the method processing blood sample that periodical paper (the human-body biological equivalence of terbinafine HCl dispersible tablet, Shi Hua, Wang Dawei etc., 2010 the 30th the 17th phases of volume of Chinese Hospitals pharmaceutical journal) is reported for work, and the production standard curve.
Two kinds of preparations intersect give 10 experimenters after, curve is referring to Fig. 1 during average medicine.The embodiment of the invention 8 is respectively (1.83 ± 0.4) mgL with the Cmax of the terbinafine HCl tablet of Comparative Examples 1 preparation
-1, (1.17 ± 0.3) mgL
-1This shows that absorbing state significantly is superior to the tablet of Comparative Examples 1 preparation in the body of terbinafine HCl tablet of the present invention.
Need to prove; The inventor is through screening that a large amount of carrier materials that prepare solid dispersion are made an experiment; The final discovery has only when carrier material adopts polyoxyethylene (40) stearate or poloxamer, and the solid dispersion tablet of preparation is stable; Dissolution is high, good absorbing effect in the body.
Claims (4)
1. a terbinafine HCl solid dispersion is characterized in that being made up of terbinafine HCl and carrier material, and wherein, the weight ratio of terbinafine HCl and carrier material is 1:2～1:15.
2. terbinafine HCl solid dispersion according to claim 1, the weight ratio that it is characterized in that terbinafine HCl and carrier material is 1:5～1:10.
3. terbinafine HCl solid dispersion according to claim 1 and 2 is characterized in that described carrier material is selected from a kind of in polyoxyethylene (40) stearate or the poloxamer.
4. the tablet that adopts the described terbinafine HCl solid dispersion of above-mentioned arbitrary claim to process is characterized in that counting by weight and includes following material:
Terbinafine HCl solid dispersion 241～360
Microcrystalline Cellulose 82～93
Carboxymethyl starch sodium 8～12
Colloidal silica 2～3
Magnesium stearate 4～4.5.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210139192.5A CN102641252B (en) | 2012-05-08 | 2012-05-08 | Terbinafine hydrochloride solid dispersoid and tablet thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210139192.5A CN102641252B (en) | 2012-05-08 | 2012-05-08 | Terbinafine hydrochloride solid dispersoid and tablet thereof |
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| CN102641252A true CN102641252A (en) | 2012-08-22 |
| CN102641252B CN102641252B (en) | 2014-06-04 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109833301A (en) * | 2017-11-29 | 2019-06-04 | 天津市保灵动物保健品有限公司 | A kind of dog cat terbinafine HCl flavor piece and its preparation process |
| CN110200929A (en) * | 2018-12-14 | 2019-09-06 | 悦康药业集团上海制药有限公司 | A kind of oral tablet and preparation method thereof containing terbinafine HCl |
| CN116139093A (en) * | 2022-12-28 | 2023-05-23 | 南京臣功制药股份有限公司 | Quick-release tablet composition containing terbinafine hydrochloride and preparation process thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1820759A (en) * | 2006-03-20 | 2006-08-23 | 复旦大学 | Tacrolimus solid dispersion and its preparing method |
| CN101505797A (en) * | 2006-08-31 | 2009-08-12 | 诺瓦提斯公司 | Pharmaceutical compositions for the treatment of fungal infections |
| CN102083420A (en) * | 2008-06-30 | 2011-06-01 | 阿伯特有限及两合公司 | Pharmaceutical dosage form comprising polymeric carrier composition |
-
2012
- 2012-05-08 CN CN201210139192.5A patent/CN102641252B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1820759A (en) * | 2006-03-20 | 2006-08-23 | 复旦大学 | Tacrolimus solid dispersion and its preparing method |
| CN101505797A (en) * | 2006-08-31 | 2009-08-12 | 诺瓦提斯公司 | Pharmaceutical compositions for the treatment of fungal infections |
| CN102083420A (en) * | 2008-06-30 | 2011-06-01 | 阿伯特有限及两合公司 | Pharmaceutical dosage form comprising polymeric carrier composition |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109833301A (en) * | 2017-11-29 | 2019-06-04 | 天津市保灵动物保健品有限公司 | A kind of dog cat terbinafine HCl flavor piece and its preparation process |
| CN110200929A (en) * | 2018-12-14 | 2019-09-06 | 悦康药业集团上海制药有限公司 | A kind of oral tablet and preparation method thereof containing terbinafine HCl |
| CN116139093A (en) * | 2022-12-28 | 2023-05-23 | 南京臣功制药股份有限公司 | Quick-release tablet composition containing terbinafine hydrochloride and preparation process thereof |
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| CN102641252B (en) | 2014-06-04 |
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