CN100496494C - Drop pills of amlodipine maleate and preparation method thereof - Google Patents
Drop pills of amlodipine maleate and preparation method thereof Download PDFInfo
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- CN100496494C CN100496494C CNB2006100100503A CN200610010050A CN100496494C CN 100496494 C CN100496494 C CN 100496494C CN B2006100100503 A CNB2006100100503 A CN B2006100100503A CN 200610010050 A CN200610010050 A CN 200610010050A CN 100496494 C CN100496494 C CN 100496494C
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- amlodipine maleate
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Abstract
The invention relates to a maleic acid amiloride horizotnal ball and relative preparation, wherein it is formed by active maleic acid amiloride horizontal and relative base; the active component is the maleic acid amiloride horizontal; the base is the carbowax 1500-20000, geoceric acid, sodium stearate, dodecyl sodium sulfate, etc; the ratio between the maleic acid amiloride horizontal and said base is 1:2-10 as g or kg; and the invention also comprises film material whose components are hydroxypropylmethylcellulose at 1.0-1.2g, titania at 0.8-1.0g, talcum powder at 1.0-1.2g, iron oxide yellow at 0.10-0.15g, sorbate-80 at 0.4-0.5g, and 80% alcohol to be 50ml. The invention has simple operation, low cost and high effect.
Description
(1) technical field
What the present invention relates to is a kind of medicine, specifically a kind of treatment hypertension and anginal medicine, particularly a kind of medicine with special form.The present invention also relates to the preparation method of the medicine of this special form.
(2) background technology
Amlodipine both can use separately as hypertension and angina pectoris treatment medicine, also can merge with other medicines such as beta-blocker or thiazide diuretic or mononitrate ester healer and use.Amlodipine provides safety widely for the patient.Heart rate there is not influence; Cardiac conduction there is not influence; In hematodinamics research, clinical dosage does not have influence to myocardial contraction; Have no adverse effects for metabolizing parameters (as blood fat, plasma insulin, blood sugar level or insulin sensitivity); There is not interaction with other common drug.For few, more common untoward reaction has edema, headache, flushing, nauseating and dizziness etc. than nifedipine, nitrendipine for the better tolerance of amlodipine, adverse reaction rate.
Amlodipine maleate is the maleate of amlodipine.Amlodipine maleate Main Ingredients and Appearance and chemical name thereof are: 3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3, its structural formula of 5-pyridine dicarboxylate maleate is: molecular formula: C20H25N205ClC4H404.Be off-white color or little yellow crystalline powder, odorless, mildly bitter flavor, stable to light, in methanol, dissolve, slightly soluble in acetone and water, almost insoluble in ethyl acetate.It is clinical to have only tablet and capsule to be applied at present.
(3) summary of the invention
Bring into play the drop pills of amlodipine maleate that curative effect, good stability are convenient to store after the object of the present invention is to provide a kind of dosage accurate, oral in vivo rapidly.The present invention also aims to provide a kind of and have easy and simple to handlely, production cost is low, can guarantee the preparation method of the drop pills of amlodipine maleate of product quality.
The object of the present invention is achieved like this: drop pill is by active constituents of medicine amlodipine maleate, substrate and the preparation of film material, and wherein the film material consists of hypromellose 1.0-1.2g, titanium dioxide 0.8-1.0g, Pulvis Talci 1.0-1.2g, iron oxide yellow 0.10-0.15g, Tween-80 0.4-0.5g
It comprises active constituents of medicine amlodipine maleate and substrate,
Active constituents of medicine is an amlodipine maleate
English name---Amlodipine Maleate
Chemical structural formula---(±)-3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-6-methyl isophthalic acid, 4-dihydro-3,5-pyridine dicarboxylate maleate
Molecular formula---C
20H
25N
2O
5ClC
4H
4O
4, molecular weight: 524.95
Substrate is the mixture of Polyethylene Glycol-6000 and poloxamer arbitrary proportion;
The proportioning of amlodipine maleate and described substrate is that unit of weight is counted 1:6 with g or Kg.
Product of the present invention can also comprise some features like this:
1, described substrate is that the weight ratio of Polyethylene Glycol-6000 and poloxamer is the mixture of 6:1.
Product of the present invention adopts following method to make:
Comprise active constituents of medicine amlodipine maleate and substrate, active constituents of medicine is an amlodipine maleate, substrate is the mixture of Polyethylene Glycol-6000 and poloxamer arbitrary proportion, and the proportioning of amlodipine maleate and described substrate is that unit of weight is counted 1:6 with g or Kg; It also comprises membrane material, membrane material consist of hypromellose 1.0-1.2g, titanium dioxide 0.8-1.0g, Pulvis Talci 1.0-1.2g, iron oxide yellow 0.10-0.15g, Tween-80 0.4-0.5g adds 80% concentration ethanol and adds to 50ml:
(1) drop pill preparation
A. raw material is crossed 100 ~ 120 mesh sieves, taken by weighing Polyethylene Glycol-6000 and poloxamer in proportion respectively, it after heat fused, is cooled to 65 ℃ of amlodipine maleates that add recipe quantity in 80 ℃ of water-baths, 60 ℃ of insulated and stirred are to even.
B. be incubated 60 ℃, adjust coolant temperature after, it is heavy to regulate ball, reaches predetermined weight, at the uniform velocity following to the dimethicone liquid coolant, dropping liquid through contraction, molding, be cured as ball, take out, blot silicone oil with filter paper, use discolour silica gel drying 48 hours
(2) film material preparation:
Get the hypromellose of proportional quantities, add an amount of 80% concentration ethanol and soak, jolting 2 hours adds titanium dioxide, Pulvis Talci, iron oxide yellow, Tween-80 more in proportion respectively, fully stirs, and adds 80% concentration ethanol again to 50ml, grinds evenly;
(3) coating process:
With the film material serosity for preparing, in boiling coating machine, it evenly is sprayed on the piller surface, and makes it dry rapidly, it is about 1% to be sprayed to weightening finish continuously, takes out, with dry 24 hours of discolour silica gel.
Product of the present invention is to adopt such method to prepare:
(1) gets the raw materials ready
Get supplementary material ready according to the ratio that contains amlodipine maleate 6-7g, Polyethylene Glycol-6000 30-40g, poloxamer 5-7g in per 1000 balls, the every ball weight drop pill that is 47-48mg; The drop pill that is 47-48mg according to per 1000 balls, every ball weight needs hypromellose 1.0-1.2g, titanium dioxide 0.8-1.0g, Pulvis Talci
1.0-1.2g, iron oxide yellow 0.10-0.15g, Tween-80 0.4-0.5g, the 80% concentration ethanol ratio that adds to 50ml gets membrane material ready;
(2) drop pill preparation
A. raw material is crossed 100 ~ 120 mesh sieves, taken by weighing Polyethylene Glycol-6000 and poloxamer in proportion respectively, it after heat fused, is cooled to 65 ℃ of amlodipine maleates that add recipe quantity in 80 ℃ of water-baths, 60 ℃ of insulated and stirred are to even.
B. be incubated 60 ℃, adjust coolant temperature after, it is heavy to regulate ball, reaches predetermined weight, at the uniform velocity following to the dimethicone liquid coolant, dropping liquid through contraction, molding, be cured as ball, take out, blot silicone oil with filter paper, use discolour silica gel drying 48 hours
(3) film material preparation:
Get the hypromellose of proportional quantities, add an amount of 80% concentration ethanol and soak, jolting 2 hours adds titanium dioxide, Pulvis Talci, iron oxide yellow, Tween-80 more in proportion respectively, fully stirs, and adds 80% concentration ethanol again to 50ml, grinds evenly;
(4) coating process:
With the film material serosity for preparing, in boiling coating machine, it evenly is sprayed on the piller surface, and makes it dry rapidly, it is about 1% to be sprayed to weightening finish continuously, takes out, with dry 24 hours of discolour silica gel.
1. prescription foundation:
It is 5mg that drop pills of amlodipine maleate calculates its content by amlodipine.Amlodipine maleate is off-white color or little yellow crystalline powder, odorless, mildly bitter flavor.This product is dissolved in methanol, slightly soluble in water or acetone, almost insoluble in ethyl acetate, belong to insoluble drug, so be developed into drop pill with solid dispersion technology, make its homodisperse in the drop pill adjuvant become ultrafine particle, increase its surface area, with quickening medicine dissolution rate, thereby improve its bioavailability.
(1) selection of carrier matrix: general first-selected water soluble polymer Polyethylene Glycol-6000, have two parallel spiral chain structures in its molecule, drug molecule can be embedded in its gap, and homodisperse, extensive use in drop pill.There are some researches show that the mixed carrier of use substrate is better than single, so select Polyethylene Glycol-6000 to be combined as mixed carrier and to prepare drop pill with poloxamer, 30 POVIDONE K 30 BP/USP 30, stearic acid respectively in the trial test.The result shows that it is favourable to molding, the smoothness of a ball to use stearic acid, but influential to dissolution, 30 POVIDONE K 30 BP/USP 30 is also similar, and it is better to use the poloxamer effect.Poloxamer is a kind of nonionic surfactant that is used for solid dispersion technology, records for Chinese Pharmacopoeia two ones of versions in 2000, is used for oral person, its molecular weight is more than 7000, and fusing point is about 53 ℃, through experiment, good with Polyethylene Glycol, the amlodipine maleate compatibility, help stripping, and do not disturb the quality testing of principal agent, secondly, its HLB value is 29, relative density 1.06, all favourable to the preparation drop pill, and safety and stability.So, select for use Polyethylene Glycol-6000 and poloxamer to be this drop pill substrate.
(2) selection of condensed fluid: according to the character of this drop pill, condensed fluid should be selected fat-soluble, as liquid Paraffin, dimethyl-silicon wet goods, through experiment, the liquid Paraffin relative density is less than normal, and (0.82 ~ 0.89g/ml), ball sedimentation is overrun, and shrinks bad, ball shape is poor, and mix use with dimethicone also not ideal; (0.96 ~ 0.98g/ml), a ball shrinks better, and ball shape rounding is selected for use so give and list is with dimethicone.
(3) feed temperature and temperature retention time are to the influence of this product its related substances: the method for preparing feed liquid by solid dispersion technology is more, general many with melting method or solvent-melting method, through preliminary experiment, it is more convenient, suitable to prepare drop pill with melting method, so select for use this method to make the manufacture method of drop pill.
When selecting for use melting method to prepare drop pill, consider the influence of temperature, through preliminary experiment to the medicine related substance, feed temperature is set to 60 ℃, 70 ℃, 80 ℃ respectively, and constant temperature keep 2h,, behind 4h, 6h, the 8h, measure the related substance of amlodipine maleate, observe its variation, the results are shown in Table 1.
Table 1 different temperatures and temperature retention time are to the influence of this product its related substances
As seen, feed temperature is not obvious to the moment influence of related substance from table 1; Same temperature is along with holding time prolonging, and the amount of related substance all has increase; Temperature is high more, and temperature retention time is long more, and the amount increase of related substance is obvious more.So in preparation during feed liquid, earlier with carrier matrix in 80 ℃ of fusings earlier, to be cooledly add amlodipine maleate during to 65 ℃, the back and be incubated 60 ℃ of drop pill of stirring, temperature retention time is advisable to be no more than 8 hours.Can guarantee that like this drop pill rounding is bright and clean, can guarantee product quality again.
(4) preparation technology is to the influence of dissolution: whether reasonably dissolution is to weigh this product prescription, technology important indicator.By experiment, having designed different process is that two kinds of approach of carrier are investigated with selecting different mixed accessories for use.The method that different process is handled is a kind of to be with direct drop pill after the auxiliary materials and mixing after crude drug and the fusion; Another kind of with after the auxiliary materials and mixing after crude drug and the fusion, cooling was ground 100 mesh sieves, the remelt drop pill rapidly.It is carrier with poloxamer, stearic acid respectively that mixed accessories is selected PEG-6000 for use.Experimental result shows: adopt different technology, and little to the dissolution influence.With PEG-6000 and poloxamer is the drop pill of mixed carrier preparation, and dissolution is about 90%; And adopt PEG-6000 and stearic acid is that the drop pill dissolution for preparing of mixed carrier is mostly about 60%.
2. the prescription and the relation of preparation process condition
(1) orthogonal test of prescription and preparation process condition
On the basis that generality is explored, select L for use
8(2
7) orthogonal test table tests, its factor and level design see Table 2, the results are shown in Table 3.
Table 2 factor and level design
Illustrate: a. crude drug is an amlodipine maleate, counts the 5mg/ ball with amlodipine; PEG is a Polyethylene Glycol-6000.
B. 7 factors are established in this experiment, 2 levels, factor A is a main matrix, consider situations such as being of moderate size of drop pill, designed 35,25 two levels, factor B, factor C consider its effect in prescription, have designed 6,3 and 3,0 each two level, and factor D, E, F and factor G have designed two levels separately on the basis of preliminary examination.
Table 3 orthogonal experiments
Illustrate: a. scoring item is the drop pill of 8 prescriptions, marks in heavy from ball respectively, ball shape, three aspects of dissolution.Whether ball is heavy: investigate drop pill and can ooze smoothly, it is heavy whether to adjust ball well; Ball shape: investigate its shaping situation; Dissolution: whether very fast stripping discharge medicine rapidly.These several aspects are more important, classify scoring item as, and the good condition of other project control can guarantee product quality.
B. standards of grading see Table 4:
Table 4 standards of grading
C. appraisal result sees Table 5:
Table 5 appraisal result
From table 3 result of the test the size of extreme difference as seen, factor C, factor D are major influence factors, next is factor A, factor B is factor F, G once more, worst is factor E.From the size of two horizontal sums, in two levels of factor A and factor B, should choose A respectively
1And B
1, factor C and factor D should select C
2And D
1, factor E should select E
2, but see E from result of extraction
1With E
2Do not have obviously difference, the metallization processes that conforms to the principle of simplicity is set out, so select E
1, factor F and factor G should select F
2And G
1, so A
1B
1C
2D
1E
1F
2G
1Be this product prescription and preparation technology's best of breed.
(2) best of breed of prescription and preparation process condition
1. the proportioning of writing out a prescription: amlodipine maleate 6.42mg, Polyethylene Glycol-6000 35mg, poloxamer 6mg
2. liquid coolant is: dimethicone
3. feed temperature is: 60 ℃
4. preparation method: direct drop pill after former, the adjuvant melting
5. coolant temperature is: 50 ℃ on top, 30 ℃ at middle part, bottom＜10 ℃
By above condition that drop pills of amlodipine maleate reagent one is small quantities of, ball shape, ball weight, uniformity of dosage units, content, dissolution, related substance etc. all meet clinical regulation with quality standard as a result.
Drop pill of the present invention as carrier, will be made solid fusant after medicine and the carrier fusion with high molecular weight water soluble polymer, keeps suitable steady temperature to drip to immiscible liquid coolant then in the drop pill machine, gets and form circular pill under surface tension effects.The drop pill used carrier is inert substance, and medicine is homodisperse in carrier, thereby the stripping, the absorption that help medicine improve curative effect: and the drop pill pill is little, is convenient to swallow and carry, and is suitable for aged patient and takes.Therefore, the present invention has easy and simple to handle, and dosage is accurate, and cost is low, brings into play drug effect in vivo rapidly after oral, characteristics such as side effect is little; And the employing film coating, make its storage-stable, not contaminated, advantage such as ensure the quality of products.
(4) specific embodiment
The specific embodiment one
(1) gets the raw materials ready
According to active constituents of medicine is amlodipine maleate, substrate is the mixture of two or more arbitrary proportion in the middle of any one or their in Polyethylene Glycol-6000, stearic acid, sodium stearate, glycerin gelatine, poloxamer, polyoxyethylene stearate 40 esters, Lac, polyoxyethylene monostearate, polyethers, carboxymethyl starch sodium or the sodium lauryl sulphate pharmaceutic adjuvant, the proportioning of amlodipine maleate and described substrate is that unit of weight is counted 1:2～10 with g or Kg; Consist of hypromellose 1.0-1.2g, titanium dioxide 0.8-1.0g, Pulvis Talci 1.0-1.2g, iron oxide yellow 0.10-0.15g, Tween-80 0.4-0.5g according to membrane material add the ratio that 80% ethanol adds to 50ml and get raw material ready;
(2) drop pill preparation
A. raw material is crossed 100 ~ 120 mesh sieves, taken by weighing Polyethylene Glycol-6000 and poloxamer in proportion respectively, it after heat fused, is cooled to 65 ℃ of amlodipine maleates that add recipe quantity in 80 ℃ of water-baths, 60 ℃ of insulated and stirred are to even.
B. be incubated 60 ℃, adjust coolant temperature after, it is heavy to regulate ball, reaches predetermined weight, at the uniform velocity following to the dimethicone liquid coolant, dropping liquid through contraction, molding, be cured as ball, take out, blot silicone oil with filter paper, use discolour silica gel drying 48 hours;
(3) film material preparation:
Get the hypromellose of proportional quantities, add an amount of 80% concentration ethanol and soak, jolting 2 hours adds titanium dioxide, Pulvis Talci, iron oxide yellow, Tween-80 more in proportion respectively, fully stirs, and adds 80% concentration ethanol again to 50ml, grinds evenly;
(4) coating process:
With the film material serosity for preparing, in boiling coating machine, it evenly is sprayed on the piller surface, and makes it dry rapidly, it is about 1% to be sprayed to weightening finish continuously, takes out, and makes product in 24 hours with the discolour silica gel drying.
The specific embodiment two
(1) gets the raw materials ready
Get supplementary material ready according to the ratio that contains amlodipine maleate 6.42g, Polyethylene Glycol-600035g, poloxamer 6g in per 1000 balls, the every ball weight drop pill that is 47.5mg; The ratio that the drop pill that is 47.5mg according to per 1000 balls, every ball weight needs hypromellose 1.0g, titanium dioxide 0.8g, Pulvis Talci 1.0g, iron oxide yellow 0.15g, Tween-80 0.4g, 80% concentration ethanol to add to 50ml is got membrane material ready;
(2) drop pill preparation
A. raw material is crossed 100 ~ 120 mesh sieves, taken by weighing Polyethylene Glycol-6000 and poloxamer in proportion respectively, it after heat fused, is cooled to 65 ℃ of amlodipine maleates that add recipe quantity in 80 ℃ of water-baths, 60 ℃ of insulated and stirred are to even.
B. be incubated 60 ℃, adjust coolant temperature after, it is heavy to regulate ball, reaches predetermined weight, at the uniform velocity following to the dimethicone liquid coolant, dropping liquid through contraction, molding, be cured as ball, take out, blot silicone oil with filter paper, use discolour silica gel drying 48 hours
(3) film material preparation:
Get the hypromellose of proportional quantities, add an amount of 80% soak with ethanol, jolting 2 hours adds titanium dioxide, Pulvis Talci, iron oxide yellow, Tween-80 more in proportion respectively, fully stirs, and adds 80% concentration ethanol again to 50ml, grinds evenly;
(4) coating process:
With the film material serosity for preparing, in boiling coating machine, it evenly is sprayed on the piller surface, and makes it dry rapidly, it is about 1% to be sprayed to weightening finish continuously, takes out, with dry 24 hours of discolour silica gel.
Claims (3)
1, a kind of drop pills of amlodipine maleate, it comprises active constituents of medicine amlodipine maleate and substrate, it is characterized in that: drop pill is by active constituents of medicine amlodipine maleate, substrate and the preparation of film material, and wherein the film material consists of hypromellose 1.0-1.2g, titanium dioxide 0.8-1.0g, Pulvis Talci 1.0-1.2g, iron oxide yellow 0.10-0.15g, Tween-80 0.4-0.5g
Active constituents of medicine is an amlodipine maleate
English name---Amlodipine Maleate
Chemical structural formula---(±)-3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-6-methyl isophthalic acid, 4-dihydro-3,5-pyridine dicarboxylate maleate
Molecular formula---C
20H
25N
2O
5ClC
4H
4O
4, molecular weight: 524.95
Substrate is the mixture of Polyethylene Glycol-6000 and poloxamer arbitrary proportion;
The proportioning of amlodipine maleate and described substrate is that unit of weight is counted 1:6 with g or Kg.
2, drop pills of amlodipine maleate according to claim 1 is characterized in that: described substrate is that the weight ratio of Polyethylene Glycol-6000 and poloxamer is the mixture of 6:1.
3, a kind of preparation method of drop pills of amlodipine maleate is characterized in that:
Drop pills of amlodipine maleate comprises active constituents of medicine amlodipine maleate and substrate, active constituents of medicine is an amlodipine maleate, substrate is the mixture of Polyethylene Glycol-6000 and poloxamer arbitrary proportion, the proportioning of amlodipine maleate and described substrate is that unit of weight is counted 1:6 with g or Kg; It also comprises membrane material, membrane material consist of hypromellose 1.0-1.2g, titanium dioxide 0.8-1.0g, Pulvis Talci 1.0-1.2g, iron oxide yellow 0.10-0.15g, Tween-80 0.4-0.5g adds 80% concentration ethanol and adds to 50ml;
(1) drop pill preparation
A. raw material is crossed 100 ~ 120 mesh sieves, take by weighing Polyethylene Glycol-6000 and poloxamer in proportion respectively, with it in 80 ℃ of water-baths after the heat fused, be cooled to 65 ℃, ratio in amlodipine maleate and Polyethylene Glycol-6000 and poloxamer substrate is the ratio adding amlodipine maleate of 1:6, and 60 ℃ of insulated and stirred are to even;
B. be incubated 60 ℃, adjust coolant temperature after, it is heavy to regulate ball, reaches predetermined weight, at the uniform velocity following to the dimethicone liquid coolant, dropping liquid through contraction, molding, be cured as ball, take out, blot silicone oil with filter paper, use discolour silica gel drying 48 hours;
(2) film material preparation:
Get the hypromellose of proportional quantities, add an amount of 80% concentration ethanol and soak, jolting 2 hours adds titanium dioxide, Pulvis Talci, iron oxide yellow, Tween-80 more in proportion respectively, fully stirs, and adds 80% concentration ethanol again to 50ml, grinds evenly;
(3) coating process:
With the film material serosity for preparing, in boiling coating machine, it evenly is sprayed on the piller surface, and makes it dry rapidly, be sprayed to weightening finish 1% continuously, take out, used discolour silica gel dry 24 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100100503A CN100496494C (en) | 2006-05-18 | 2006-05-18 | Drop pills of amlodipine maleate and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100100503A CN100496494C (en) | 2006-05-18 | 2006-05-18 | Drop pills of amlodipine maleate and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1879621A CN1879621A (en) | 2006-12-20 |
| CN100496494C true CN100496494C (en) | 2009-06-10 |
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|---|---|---|---|
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| CN109432033B (en) * | 2018-12-26 | 2021-03-30 | 成都恒瑞制药有限公司 | Amlodipine besylate dripping pill and its prepn |
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