CN102462844A - Tilisolol pharmaceutical composition and its preparation method - Google Patents
Tilisolol pharmaceutical composition and its preparation method Download PDFInfo
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- CN102462844A CN102462844A CN2010105321119A CN201010532111A CN102462844A CN 102462844 A CN102462844 A CN 102462844A CN 2010105321119 A CN2010105321119 A CN 2010105321119A CN 201010532111 A CN201010532111 A CN 201010532111A CN 102462844 A CN102462844 A CN 102462844A
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- tilisolol
- stabilizing agent
- mix homogeneously
- pharmaceutical composition
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Abstract
The invention discloses a tilisolol pharmaceutical composition, which contains an active component tilisolol hydrochloride, a stabilizing agent and other pharmaceutically acceptable auxiliary materials. The stabilizing agent contains one or more components selected from calcium oxide, calcium hydrate and magnesium hydroxide. The weight ratio of the stabilizing agent to the active component tilisolol hydrochloride is 0.10:1 to 10:1 and preferably 0.2-2:1. The invention also discloses a method for preparing the pharmaceutical composition.
Description
Technical field
the present invention relates to pharmaceutical composition of a kind of tilisolol and preparation method thereof.The solid preparation that particularly relates to a kind of N-696, like tablet, capsule and granule etc., and preparation method thereof.
Background technology
hypertension is modal cardiovascular diseases, also is the great public health problem in the global range, and prevalence reaches about 10%, the developed country that has even reach 20%, and there are about 600,000,000 people of hyperpietic in the whole world.China has become the higher country of hypertension incidence rate at present, and sickness rate rises with bigger ratio always in nearly 20 years.From now on, along with the continuous quickening of social life rhythm, physical work will reduce day by day, and dietary structure is tending towards the high fat of hyperpyrexia, and the trend that hyperpietic's number obviously rises will continue in for a long time.
N-696 ((±)-4-(3-tert-butylamine base-2-hydroxyl propoxyl group)-2-methyl isophthalic acid (2H)-isoquinolines hydrochlorate) (formula I) is a non-selective beta-blocker of new generation, and indication is light, moderate essential hypertension and angina pectoris.This medicine eliminate half-life length be 12 hours, oral administration only need is the novel representative of long-acting antihypertensive drug once a day, especially in the anginal treatment of hypertensive patients, has more advantage.
since 4-(the 3-tert-butylamine base-2-hydroxyl propoxyl group) group in the N-696 molecular structure be prone to from the parent disengaging of dissociating; Medicine stability is poor, and many common solid preparation pharmaceutical excipients all can quicken the degraded of N-696, therefore; Adopt common pharmacy preparation forming technique to be difficult to prepare the N-696 solid preparation that meets drug standard; Like tablet, capsule, granule etc.
Summary of the invention
are through research; We unexpectedly find, after earlier principal agent N-696 and certain amount of stabilizer being mixed, again with other solid preparation molding excipient; Mixed like hydroxypropyl cellulose, carboxymethyl starch sodium, lactose etc.; Prepared N-696 oral solid formulation has good stable property like tablet, capsule, granule etc., can solve the technical problem that the principal agent N-696 is prone to degraded.Stabilizing agent wherein is selected from a kind of in calcium oxide, calcium hydroxide, the magnesium hydroxide or wherein several kinds.
the purpose of this invention is to provide a kind of N-696 that makes and keep stable Pharmaceutical composition.Said composition comprises a. active ingredient hydrochloric acid tilisolol; B. stabilizing agent; C. other solid preparation molding adjuvant hydroxypropyl cellulose, carboxymethyl starch sodium, lactose, magnesium stearate, sclerosis wet goods.Stabilizing agent wherein is selected from one or more in calcium oxide, calcium hydroxide, the magnesium hydroxide.The weight ratio of itself and active ingredient hydrochloric acid tilisolol is 0.10:1 to 10:1, is preferably 0.2:1 to 2:1.
another object of the present invention provides a kind of method for preparing that makes the stable Pharmaceutical composition of N-696 maintenance.Earlier with principal agent N-696 and certain amount of stabilizer; Like a kind of of calcium oxide, calcium hydroxide, magnesium hydroxide etc. or wherein several kinds mixed after; With other solid preparation molding excipient, mixed again like hydroxypropyl cellulose, carboxymethyl starch sodium, lactose etc.; (1) be that wetting agent carries out wet granulation with non-water-soluble matchmaker, the granule of preparation sieves after drying, and with the mixed back of magnesium stearate tabletting, perhaps the fill capsule perhaps prepares granule; Perhaps (2) adopt dry granulation direct compression process or direct powder compression to prepare tablet.Said method for preparing specifically comprises:
1) get active ingredient hydrochloric acid tilisolol and certain amount of stabilizer (calcium oxide, calcium hydroxide, magnesium hydroxide etc. a kind of or wherein several kinds), cross 40 order to 80 mesh sieve mix homogeneously.Get a certain amount of other solid preparation molding adjuvant again,, add wherein, and cross 40 order to 80 mesh sieve mix homogeneously like hydroxypropyl cellulose, carboxymethyl starch sodium, lactose etc.
2) use non-water-soluble matchmaker to be wetting agent, with above-mentioned mixed material system soft material, cross 18 order to 20 mesh sieve system wet granulars, 40 ℃ to 60 ℃ on wet granular warp is dry must do granule.Wherein non-water-soluble matchmaker is a kind of in ethanol, the acetone, is preferably ethanol.
3) in dried granule, add a certain amount of lubricant; It is mixed to cross 14 order to 16 mesh sieves; Granulate; Contain the tablet that the principal agent N-696 is 10mg or 20mg according to clinical application demand compacting, perhaps directly the fill capsule prepares the capsule of 10mg or 20mg specification, and perhaps to become specification be the granule of 10mg or 20mg to direct packaging.Wherein lubricant is preferably a kind of in magnesium stearate, fixed oil, the Pulvis Talci or wherein several kinds, and consumption is 0.5% to 2.0% of whole weight of material.
4) also can be with 1) the supplementary material mixture of preparation; With a certain amount of lubricant mixed after; Adopt dry granulation technology or technique of direct powder compression, directly prepare tablet or the capsule that specification is 10mg or 20mg without wet-granulation process.Wherein lubricant is preferably a kind of in magnesium stearate, fixed oil, the Pulvis Talci or wherein several kinds, and consumption is 0.5% to 2.0% of whole weight of material.
The specific embodiment
Through the specific embodiment the present invention is further specified below
.Here want to be pointed out that; Below the specific embodiment only be used for explaining the present invention; Those skilled in the art are understanding under the prerequisite of spirit of the present invention; Can carry out corresponding conversion to the present invention according to the prior art and the knowledge in present technique field, these technical schemes all fall within the scope of the present invention.
Embodiment 1 does stabilizing agent hydrochloric acid tilisolol tablet and capsular preparation with calcium oxide
Prescription:
Preparation technology:
take by weighing supplementary material according to formula proportion; At first that N-696 and calcium oxide is mixed and cross 60 mesh sieves to mix homogeneously; Mixed and cross 60 mesh sieves with hydroxypropyl cellulose again to mix homogeneously; Mixed and cross 60 mesh sieves with lactose again to mix homogeneously, last mix with magnesium stearate and fixed oil and 60 mesh sieve mix homogeneously.It is 10mg that direct powder compression prepares specification, and sheet heavily is 120mg, and sheet directly is the N-696 tablet of 7mm (also directly No. 3 capsules of fill prepare the N-696 capsule that specification is 10mg).
Embodiment 2 does stabilizing agent hydrochloric acid tilisolol tablet and capsular preparation with calcium hydroxide
Prescription:
Preparation technology:
take by weighing supplementary material according to formula proportion; At first that N-696 and calcium hydroxide is mixed and cross 60 mesh sieves to mix homogeneously; Mixed and cross 60 mesh sieves with hydroxypropyl cellulose again to mix homogeneously; Mixed and cross 60 mesh sieves with lactose again to mix homogeneously, last mix with magnesium stearate and fixed oil and 60 mesh sieve mix homogeneously.It is 10mg that direct powder compression prepares specification, and sheet heavily is 120mg, and sheet directly is the N-696 tablet of 7mm (also directly No. 3 capsules of fill prepare the N-696 capsule that specification is 10mg).
Embodiment 3 does stabilizing agent hydrochloric acid tilisolol tablet and capsular preparation with magnesium hydroxide
Prescription:
Preparation technology:
take by weighing supplementary material according to formula proportion; At first that N-696 and magnesium hydroxide is mixed and cross 60 mesh sieves to mix homogeneously; Mixed and cross 60 mesh sieves with hydroxypropyl cellulose again to mix homogeneously; Mixed and cross 60 mesh sieves with lactose again to mix homogeneously, last mix with magnesium stearate and fixed oil and 60 mesh sieve mix homogeneously.It is 10mg that direct powder compression prepares specification, and sheet heavily is 120mg, and sheet directly is the N-696 tablet of 7mm (also directly No. 3 capsules of fill prepare the N-696 capsule that specification is 10mg).
Comparative example 1 does stabilizing agent hydrochloric acid tilisolol tablet and capsular preparation with magnesium silicate
Prescription:
Preparation technology:
take by weighing supplementary material according to formula proportion; At first that N-696 and magnesium silicate is mixed and cross 60 mesh sieves to mix homogeneously; Mixed and cross 60 mesh sieves with hydroxypropyl cellulose again to mix homogeneously; Mixed and cross 60 mesh sieves with lactose again to mix homogeneously, last mix with magnesium stearate and fixed oil and 60 mesh sieve mix homogeneously.It is 10mg that direct powder compression prepares specification, and sheet heavily is 120mg, and sheet directly is the N-696 tablet of 7mm (also directly No. 3 capsules of fill prepare the N-696 capsule that specification is 10mg).
Comparative example 2 does stabilizing agent hydrochloric acid tilisolol tablet and capsular preparation with magnesium oxide
Prescription:
Preparation technology:
take by weighing supplementary material according to formula proportion; At first that N-696 and magnesium oxide is mixed and cross 60 mesh sieves to mix homogeneously; Mixed and cross 60 mesh sieves with hydroxypropyl cellulose again to mix homogeneously; Mixed and cross 60 mesh sieves with lactose again to mix homogeneously, last mix with magnesium stearate and fixed oil and 60 mesh sieve mix homogeneously.It is 10mg that direct powder compression prepares specification, and sheet heavily is 120mg, and sheet directly is the N-696 tablet of 7mm (also directly No. 3 capsules of fill prepare the N-696 capsule that specification is 10mg).
Comparative example 3 does stabilizing agent hydrochloric acid tilisolol tablet and capsular preparation with hydroxypropyl cellulose
Prescription:
Preparation technology:
take by weighing supplementary material according to formula proportion; N-696 and hydroxypropyl cellulose is mixed and cross 60 mesh sieves to mix homogeneously; Mixed and cross 60 mesh sieves with lactose again to mix homogeneously, last mix with magnesium stearate and fixed oil and 60 mesh sieve mix homogeneously.It is 10mg that direct powder compression prepares specification, and sheet heavily is 120mg, and sheet directly is the N-696 tablet of 7mm (also directly No. 3 capsules of fill prepare the N-696 capsule that specification is 10mg).
Test Example 1 determination of related substances method (HPLC)
chromatographic condition: immobile phase is Allsphere C18 post (5mm; 4.6mm * 250mm), mobile phase is for (the 0.8g sodium lauryl sulphate is dissolved in the 550ml water, adds the 0.55ml glacial acetic acid; PH value is about 3.15-3.2); The detection wavelength is 220nm, and flow velocity is 1ml/min, and sample size is 20ml.
related substance (catabolite) algoscopy: get 10 of test specimens, in the 100ml measuring bottle, it is an amount of to add mobile phase, and jolting makes the principal agent dissolving, adds mobile phase to scale, with the organic membrane filtration of 0.45 μ m.Get subsequent filtrate as need testing solution.Get need testing solution 20 μ l, the injection chromatograph of liquid, 3 times of writing down chromatogram to retention time are pressed the peak area normalization method and are measured its amount of degradation products (%).
Experimental example 2 unpackaged high-temperature sample high humidity influence factor stability relatively
are with embodiment and comparative example's naked 60 ℃ of the high temperature that place of all prescription samples (prescription 1 is to prescription 21); Under the relative humidity RH75% condition; Respectively at sampling in 0 day, 1 day, 3 days, 5 days; The appearance color of observing preparation changes, and the method for employing Test Example 1 is measured the variation of the amount of its catabolite (related substance).The result sees table 1 to table 6.
The table 1 embodiment 1 stability of sample result that respectively fills a prescription
The table 2 embodiment 2 stability of sample result that respectively fills a prescription
The table 3 embodiment 3 stability of sample result that respectively fills a prescription
The table 4 comparative example 1 stability of sample result that respectively fills a prescription
The table 5 comparative example 2 stability of sample result that respectively fills a prescription
Table 6 comparative example 3 prescription stability of sample results
Experimental example 3 adds the hot and humid stability test that compound aluminium strip packs sample through the plastic-aluminum bubble-cap
are with filling a prescription 3 among the embodiment 1, filling a prescription 11 among prescription 7 and the embodiment 3 among the embodiment 2; And fill a prescription 15 among the comparative example 1, the product of prescription 21 among prescription 19 and the comparative example 3 among the comparative example 2; Add after compound aluminium strip packs with the plastic-aluminum bubble-cap; High temperature (60 ℃) high humiditys (RH75%) condition held 3 months; In 0,1,2, March sample analysis, the appearance color of observing preparation changes, and adopts the method for Test Example 1 to investigate the variation of the amount of its catabolite (related substance).The result sees table 7.
Table 7 through the plastic-aluminum bubble-cap add compound aluminium strip pack after the stability of sample result
Claims (7)
1.
a kind of N-696 pharmaceutical composition contains active ingredient hydrochloric acid tilisolol, stabilizing agent and other pharmaceutically acceptable adjuvant; Wherein said stabilizing agent is selected from a kind of of calcium oxide, calcium hydroxide, magnesium hydroxide etc. or wherein several kinds.
2.
according to the pharmaceutical composition of claim 1, the weight ratio that it is characterized in that stabilizing agent and active ingredient hydrochloric acid tilisolol is 0.10:1 to 10:1.
3.
according to the pharmaceutical composition of claim 2, the weight ratio that it is characterized in that stabilizing agent and active ingredient hydrochloric acid tilisolol is 0.2-2:1.
4.
is characterized in that according to the pharmaceutical composition of claim 1 described pharmaceutically acceptable adjuvant is selected from hydroxypropyl cellulose, carboxymethyl starch sodium, lactose, magnesium stearate, fixed oil.
5.
According to the described preparation of drug combination method of each claim among the claim 1-4, this method comprises:
1) gets active ingredient hydrochloric acid tilisolol and stabilizing agent, cross 40 order to 80 mesh sieve mix homogeneously; Get other adjuvant again, add wherein, and the mix homogeneously that sieves;
2) use non-water-soluble matchmaker to be wetting agent, with above-mentioned mixed material system soft material, cross 18 order to 20 mesh sieve system wet granulars, 40 ℃ to 60 ℃ on wet granular warp is dry must do granule; Wherein non-water-soluble matchmaker is selected from ethanol, acetone;
3) in dried granule, add lubricant, it is mixed to cross 14 order to 16 mesh sieves, and granulate is processed preparation.
6.
According to the described preparation of drug combination method of each claim among the claim 1-4, comprising:
1) gets active ingredient hydrochloric acid tilisolol and stabilizing agent, cross 40 order to 80 mesh sieve mix homogeneously; Get other adjuvant again, add wherein, and the mix homogeneously that sieves;
2) with the supplementary material mixture, with lubricant mixed after, adopt dry granulation technology or technique of direct powder compression to process preparation.
7.
according to the method for preparing of claim 5 or 6, and wherein said lubricant is a kind of in magnesium stearate, fixed oil, the Pulvis Talci or wherein several kinds, and consumption is 0.5% to 2.0% of whole weight of material.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105321119A CN102462844A (en) | 2010-11-05 | 2010-11-05 | Tilisolol pharmaceutical composition and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105321119A CN102462844A (en) | 2010-11-05 | 2010-11-05 | Tilisolol pharmaceutical composition and its preparation method |
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| CN102462844A true CN102462844A (en) | 2012-05-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2010105321119A Pending CN102462844A (en) | 2010-11-05 | 2010-11-05 | Tilisolol pharmaceutical composition and its preparation method |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1422161A (en) * | 2000-04-03 | 2003-06-04 | 阿斯特拉曾尼卡有限公司 | New combination of a beta blocker and a cholesterol-lowering agent |
| CN1686549A (en) * | 2005-05-08 | 2005-10-26 | 广州市施柏医药科技有限公司 | Medicinal composition for treating high blood pressure |
-
2010
- 2010-11-05 CN CN2010105321119A patent/CN102462844A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1422161A (en) * | 2000-04-03 | 2003-06-04 | 阿斯特拉曾尼卡有限公司 | New combination of a beta blocker and a cholesterol-lowering agent |
| CN1686549A (en) * | 2005-05-08 | 2005-10-26 | 广州市施柏医药科技有限公司 | Medicinal composition for treating high blood pressure |
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Application publication date: 20120523 |