CN101862337B - Drug composite containing limaprost and preparation method thereof - Google Patents
Drug composite containing limaprost and preparation method thereof Download PDFInfo
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Abstract
The invention provides a drug composite containing limaprost and a preparation method thereof, wherein the drug composite of the invention contains 0.01-1% (weight) of the cyclodextrin inclusion compound of limaprost, 0.5-10% (weight) of freeze-drying stabilizer and other pharmaceutically acceptable excipients, wherein the free-drying stabilizer contains mannitol. The drug composite adopts a freeze drying and dry granulating combined preparation technology, greatly overcomes the defects of easy moisture adsorption and extremely bad stability of limaprost which is the main drug, and simultaneously cannot influence the slaking characteristic and the dissolution of the main drug, in addition, the product is not a coated tablet, and thereby the invention prevents the defect of slower dissolution of the conventional coated tablets.
Description
Technical field
The invention belongs to field of pharmaceutical preparations,, particularly relate to a kind of oral limaprost sheet and preparation method thereof that is used in particular to a kind of pharmaceutical composition and preparation method thereof.
Background technology
Limaprost (Limaprost) chemical name is: (E)-and 7-[(1R; 2R, 3R)-3-hydroxyl-2-[(3S, 5S)-(E)-3-hydroxy-5-methyl base-1-nonene base]-the 5-oxocyclopentyl]-2-enanthic acid ((E)-7-[(1R; 2R; 3R)-3-hydroxy-2-[(3S, 5S)-(E)-3-hydroxy-5-methyl-1-nonenyl]-5-oxocyclopenty1]-2-heptenoic acid), structural formula is as follows:
These article are the derivant of PGE1; Can increase cyclic adenosine monophosphate (cAMP) content, suppress thromboxane A2 (TXA2) generation; Have vasodilation, increasing blood flow and inhibition platelet aggregation and adherent effect, zoopery also shows can increase nervous tissue's blood flow, improve nervous function.Be used to clinically improve all kinds of ischemic symptoms that thromboangiitis obliterans causes, like ulcer, pain, creeping chill; And improve posteriority lumbar spinal stenosis (subjective symptom (pain and feeling of numbness) and the locomotor activity of straight-leg raising test (straight leg raising test, SLR) normal intermittent claudication patient).
The cyclodextrin clathrate of limaprost is white powder, and is soluble in water, and the atomic ethanol (95%) that is dissolved in is dissolved in ethyl acetate and diethyl ether hardly.Has the tide of drawing property.Chemical property is very unstable, and is very responsive to pH, moisture and humidity.Because traditional PGE1 (PGE
1) be prone to the metabolism that is decomposed at gastrointestinal tract, can not oral administration, adopt drug administration by injection usually, brought great inconvenience to the patient.Therefore, have and PGE
1The limaprost of similar pharmacologically active and orally-ingestible has received extensive concern, but because the physicochemical property of limaprost is extremely unstable, adopts conventional method to be difficult to make oral formulations, has therefore brought very big difficulty and challenge to research and development.
Japan Patent (spy opens 2005-139085) discloses limaprost granule and preparation method thereof, prepares required granule through adding water-soluble high-molecular substance; Japan Patent (spy opens 2005-139086) discloses the limaprost oral cavity disintegration tablet.Patent publication No. is that the patent of KR20080099562 discloses solid dispersion that contains limaprost or its cyclodextrin clathrate carrier and preparation method thereof.At present, the domestic any patent application that does not also have about limaprost.
Freeze Drying Technique is to be frozen into solid to the material that contains large quantity of moisture in advance; Under vacuum condition, suitably heating then makes steam directly from solid, distil; And material itself is stayed in ice shelf when freezing, and the volume of therefore dry back product is almost constant.Whole drying is under lower temperature, to carry out.Cryodesiccated advantage mainly contains: degeneration or inactivation can not take place to many heat-sensitive substance particularly suitables like protein, microorganism etc. in frozen drying; During frozen drying, the loss of product volatile component is little; In the frozen drying process, can effectively suppress the effect of microbial growth and enzyme; Frozen drying has guaranteed original structure of product basically, concentration phenomena can not take place; Dried product is loose porous to be spongy, dissolves after adding water, can return to the original form rapidly; Basic oxygen-free gas during vacuum drying, so the material of some easy oxidations is protected; Frozen drying can be got rid of the moisture more than 95%, and dried product can long preservation never degenerate.
Summary of the invention
In order to improve the extremely unsettled physicochemical property of limaprost; The inventor is through concentrating on studies; Prescription composition to preparation has carried out a large amount of screenings; Adopt lyophilization and dry granulation combined preparation technology, temperature, humidity and pressure condition in each step preparation process of strict control have prepared the limaprost sheet that has high stability, can be oral.
The purpose of this invention is to provide a kind of pharmaceutical composition that comprises limaprost and preparation method thereof.
For realizing the foregoing invention purpose, the present invention has adopted following technical scheme:
A kind of pharmaceutical composition that comprises limaprost, this pharmaceutical composition comprise lyophilizing stabilizing agent and other pharmaceutically acceptable excipient of cyclodextrin clathrate, 0.5% (weight)～10% (weight) of the limaprost of 0.01% (weight)～1% (weight); Wherein, said lyophilizing stabilizing agent comprises mannitol.
Aforementioned pharmaceutical compositions can comprise the lubricant of filler and 0.3 (weight) %～2% (weight) of disintegrating agent, 40% (weight)～88% (weight) of binding agent, 5% (weight)～25% (weight) of lyophilizing stabilizing agent, 5% (weight)～30% (weight) of cyclodextrin clathrate, 0.5% (weight)～10% (weight) of the limaprost of 0.01% (weight)～1% (weight); Wherein, said lyophilizing stabilizing agent comprises mannitol.
In the aforementioned pharmaceutical compositions, the cyclodextrin in the cyclodextrin clathrate of said limaprost can be selected from one or more among α-CD, β-CD, γ-CD, hydroxypropyl-α-CD, hydroxy propyl-Beta-CD, hydroxypropyl-γ-CD, carboxymethyl-β-CD, dimethyl-β-CD and the tertbutyl ether-β-CD.
In the aforementioned pharmaceutical compositions, said lyophilizing stabilizing agent can also comprise other saccharides, for example in sorbitol, trehalose, lactose and the sucrose one or more; Preferably, the mass ratio of mannitol and other saccharides described in the said lyophilizing stabilizing agent can be 1: 5～10: 1.
In the aforementioned pharmaceutical compositions, said binding agent can be selected from one or more in polyvidone, hypromellose, pectin, tragacanth, xanthan gum, arabic gum, guar gum, dextrin, sodium carboxymethyl cellulose and the starch slurry.
In the aforementioned pharmaceutical compositions, said disintegrating agent can be selected from one or more in low-substituted hydroxypropyl cellulose, starch, polyvidone, microcrystalline Cellulose, carboxymethyl starch sodium and the polyvinylpolypyrrolidone.
In the aforementioned pharmaceutical compositions, said filler can be in lactose, glucose, maltose, glycine and the soluble dextrins one or more.
In the aforementioned pharmaceutical compositions, said lubricant can be selected from one or more in magnesium stearate, sodium stearyl fumarate, stearic acid, Pulvis Talci and the micropowder silica gel.
A kind of method for preparing aforementioned pharmaceutical compositions, this method for preparing comprises the steps:
(a) take by weighing the lyophilizing stabilizing agent of cyclodextrin clathrate and 0.5% (weight)～10% (weight) of the limaprost of 0.01% (weight)～1% (weight), with the suitable quantity of water dissolving, lyophilization makes freeze-dried mixture I;
(b) the freeze-dried mixture I that step (a) is made pulverizes; Sieve; The lubricant of filler and 0.15 (weight) %～1% (weight) of the disintegrating agent, 40% (weight)～88% (weight) of the binding agent, 5% (weight)～25% (weight) of adding 5% (weight)～30% (weight); Mix, make mixtures II;
(c) mixtures II that step (b) is made places in the dry granulation machine and granulates, and adds the lubricant of 0.15 (weight) %～1% (weight), mixes, and makes mixtures III, places the vacuum drier inner drying;
(d) with the dried mixtures III tabletting of step (b), promptly get said compositions;
Wherein, said lyophilizing stabilizing agent comprises mannitol.
In the step of above-mentioned method for preparing (a), cryodesiccated condition is: the pre-freeze temperature is-10 ℃～-40 ℃, and the pressure≤500Pa of evacuation, the temperature of evacuation are-10 ℃～-30 ℃, and baking temperature is 0-30 ℃, drying pressure≤in 500Pa.
According to a specific embodiments of the present invention, preparation of drug combination method of the present invention comprises the steps:
(a) take by weighing the lyophilizing stabilizing agent of cyclodextrin clathrate and 0.5% (weight)～10% (weight) of the limaprost of 0.01% (weight)～1% (weight), with an amount of water dissolution, lyophilization makes freeze-dried mixture I;
Wherein, cryodesiccated condition is: the pre-freeze temperature is-10 ℃～-40 ℃; Pressure≤the 500Pa of evacuation, the temperature of evacuation are-10 ℃～-30 ℃; Drying condition is 0-30 ℃, drying pressure≤500Pa
Wherein, said lyophilizing stabilizing agent comprises mannitol;
(b) the freeze-dried mixture I that step (a) is made pulverizes or micronizing; Cross 100 mesh sieves; The filler of the disintegrating agent and 40% (weight)～90% (weight) of the binding agent, 5% (weight)～25% (weight) of adding 5% (weight)～30% (weight) mixed more than 5 minutes, added the lubricant of 0.15 (weight) %～1% (weight) again; Mix more than 1 minute, make mixtures II;
(c) mixtures II that step (b) is made places in the dry granulation machine and granulates, and in the lubricant adding granule with 0.15 (weight) %～1% (weight), mixes more than 1 minute, makes mixtures III, places the vacuum drier inner drying;
(d) the dried mixtures III of step (b) is adopted the tablet machine tabletting, place the vacuum drier inner drying, the tablet that makes carries out aluminum-plastic packaged, together wraps into Aluminum-plastic composite bag with medicinal desiccant again, gets final product.
Compared with prior art, the present invention has following beneficial effect at least:
(1) the present invention has adopted lyophilization and dry granulation combined preparation technology, has overcome the very easily moisture absorption of principal agent limaprost, this particular disadvantages of stable extreme difference greatly, does not influence disintegrate simultaneously, does not also influence the stripping of principal agent composition.
(2) comprise mannitol in the lyophilizing stabilizing agent of the present invention; The pharmaceutical composition stability that makes is high; Compare with the product that commercially available Japanese ocean company produces, greatly improved the important factor in order that influences the micro-quality of the pharmaceutical preparations--the tablet content uniformity and stability.Pharmaceutical composition of the present invention is not a coated tablet, has avoided the slower shortcoming of conventional coated tablet stripping.
(3) the limaprost tablet that makes of the present invention is compared with marketed tablet, hardness is significantly improved, and has overcome that the limaprost tablet that technology in the past makes is soft partially, frangible shortcoming in the packing, storage, transportation.
(4) the limaprost sheet stripping curve of the present invention preparation is stable, the uniform content between sheet and the sheet, and medicine rapid-action, release is stably in vivo after this compared with the preparation that previous methods makes, and can significantly improve intravital bioavailability.
Description of drawings
Fig. 1 is the stripping release curve chart of the limaprost sheet of embodiment 1～embodiment 6.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention., these embodiment are not used in restriction scope of the present invention but only limiting to the present invention is described.The experimental technique of unreceipted concrete experiment condition in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1
The prescription of pharmaceutical composition of the present invention--limaprost sheet is formed:
Limaprost hydroxypropyl-α-CD clathrate 0.17g
Mannitol 0.72g
Sorbitol 1.78g
Starch slurry 7.00g
Polyvidone 4.50g
Lactose 70.23g
Pulvis Talci 0.60g
Process tablet 85mg/ sheet, process 1000
Method for preparing:
A, take by weighing 0.72g mannitol, 1.78g sorbitol and 0.17g limaprost hydroxypropyl-α-CD clathrate; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-40 ℃; 200Pa ,-20 ℃ of following evacuation, 100Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 7.00g starch slurry, 4.50g polyvidone, 70.23g lactose, mix more than 5 minutes, add the Pulvis Talci of 0.30g again, mix more than 1 minute, get mixtures II by the prescription ratio;
C, mixtures II put in the dry granulation machine granulates, remaining Pulvis Talci is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
Testing result is following:
(1) tablet that according to said method prepares, hardness is 3.0kg;
(2) tablet that according to said method prepares, be 3 minutes and 52 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 99%.
Wherein, hardness detection method: adopt YD-2 hardness-testing device (optical instrument factory, Tianjin) to measure.
The detection method of disintegration: the method according under 2005 editions two appendix XA inspection techniques disintegration of the Chinese Pharmacopoeia item is checked.
The detection method of dissolution: get 6 of these article; Adopting the oar method according to dissolution method (2005 editions two appendix XC three therapeutic methods of traditional Chinese medicine of Chinese Pharmacopoeia), is dissolution medium with 500ml water, and rotating speed is that per minute 50 commentaries on classics are operated; In the time of 45 minutes, get solution 100 μ l and inject the liquid chromatograph sample introduction.It is an amount of that other gets the limaprost reference substance, processes the solution of 0.5 μ g/ml with dehydrated alcohol, and precision is measured this solution 1ml and placed the 10ml volumetric flask, and thin up to scale promptly gets reference substance solution, measures with method, calculates every stripping quantity.Limit is 80% of a labelled amount.
Embodiment 2
The prescription of limaprost sheet is formed:
Limaprost hydroxypropyl-γ-CD clathrate 0.0125g
Mannitol 0.70g
Trehalose 0.70g
Pectin 4.50g
Carboxymethyl starch sodium 8.00g
Maltose 70.08g
Magnesium stearate 1.00g
Process tablet 85mg/ sheet, process 1000
Method for preparing:
A, the mannitol that takes by weighing 0.70g, 0.70g trehalose and 0.0125g limaprost hydroxypropyl-γ-CD clathrate; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-30 ℃; 300Pa ,-20 ℃ of following evacuation, 200Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 4.50g pectin, 8.00g carboxymethyl starch sodium, 70.08g maltose, mix more than 5 minutes, add the magnesium stearate of 0.50g again, mix more than 1 minute, get mixtures II by the prescription ratio;
C, mixtures II put in the dry granulation machine granulates, remaining magnesium stearate is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
Detection method with reference to hardness detection method, the detection method of disintegration and the dissolution of embodiment 1 detects, and testing result is following:
(1) tablet that according to said method prepares, hardness is 3.5kg;
(2) tablet that according to said method prepares, be 4 minutes and 13 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 105%.
Embodiment 3
The prescription of limaprost sheet is formed:
Limaprost-α-CD clathrate 0.25g
Mannitol 0.75g
Sucrose 0.25g
Hydroxypropyl methylcellulose 10.00g
Low-substituted hydroxypropyl cellulose 10.00g
Sorbitol 63.25g
Micropowder silica gel 0.50g
Process tablet 85mg/ sheet, process 1000
Method for preparing:
A, the mannitol that takes by weighing 0.75g, 0.25g sucrose and 0.25g limaprost-α-CD clathrate, with an amount of water dissolution, lyophilization, the pre-freeze temperature is-20 ℃, 65Pa ,-30 ℃ of following evacuation, 90Pa, 30 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, by prescription ratio adding 10.00g hydroxypropyl methylcellulose, 10.00g low-substituted hydroxypropyl cellulose, 63.25g sorbitol; Mix more than 5 minutes; The micropowder silica gel that adds 0.25g again mixed more than 1 minute, got mixtures II;
C, mixtures II put in the dry granulation machine granulates, remaining micropowder silica gel is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
Detection method with reference to hardness detection method, the detection method of disintegration and the dissolution of embodiment 1 detects, and testing result is following:
(1) tablet that according to said method prepares, hardness is 2.9kg;
(2) tablet that according to said method prepares, be 4 minutes and 27 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 103%.
Embodiment 4
The prescription of limaprost sheet is formed:
Limaprost carboxymethyl-beta-CD inclusion 0.60g
Mannitol 5.83g
Lactose 1.17g
Arabic gum 20.00g
Crospovidone 5.00g
Glycine soluble dextrins 50.90g
Stearic acid 1.50g
Process tablet 85mg/ sheet, process 1000
Method for preparing:
A, the mannitol that takes by weighing 5.83g, 1.17g lactose and 0.60g limaprost carboxymethyl-beta-CD inclusion; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-20 ℃; 350Pa ,-15 ℃ of following evacuation, 400Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, by prescription ratio adding 20.00g arabic gum, 5.00g crospovidone, 50.90g glycine soluble dextrins; Mix more than 5 minutes; The stearic acid that adds 0.75g again mixed more than 1 minute, got mixtures II;
D, mixtures II put in the dry granulation machine granulates, remaining stearic acid is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
E, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
F, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
Detection method with reference to hardness detection method, the detection method of disintegration and the dissolution of embodiment 1 detects, and testing result is following:
(1) tablet that according to said method prepares, hardness is 3.5kg;
(2) tablet that according to said method prepares, be 4 minutes and 36 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 104%.
The prescription of limaprost sheet is formed:
Limaprost dimethyl-beta-CD inclusion 0.30g
Mannitol 5.68g
Sucrose 0.82g
Dextrin 15.00g
Carboxymethyl starch sodium 5.00g
Glucose 57.20g
Sodium stearyl fumarate 1.00g
Process tablet 85mg/ sheet, process 1000
Method for preparing:
A, the dextran that takes by weighing 5.68g, 0.82g mannitol and 0.30g limaprost dimethyl-beta-CD inclusion; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-25 ℃; 75Pa ,-20 ℃ of following evacuation, 100Pa, 30 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 15.00g dextrin, 5.00g carboxymethyl starch sodium, 57.20g glucose, mix more than 5 minutes, add the sodium stearyl fumarate of 0.50g again, mix more than 1 minute, get mixtures II by the prescription ratio;
C, mixtures II put in the dry granulation machine granulates, remaining sodium stearyl fumarate is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
Detection method with reference to hardness detection method, the detection method of disintegration and the dissolution of embodiment 1 detects, and testing result is following:
(1) tablet that according to said method prepares, hardness is 3.3kg;
(2) tablet that according to said method prepares, be 4 minutes and 43 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 97%.
Embodiment 6
The prescription of limaprost sheet is formed:
Limaprost α-CD clathrate 0.08g
Mannitol 4.5g
Trehalose 0.5g
Tragacanth 7.50
Microcrystalline Cellulose 20.00g
Lactose 51.62g
Magnesium stearate 0.80g
Process tablet 85mg/ sheet, process 1000
Method for preparing:
A, the mannitol that takes by weighing 4.50g, 0.5g trehalose and 0.08g limaprost γ-CD clathrate, with an amount of water dissolution, lyophilization, the pre-freeze temperature is-35 ℃, 100Pa ,-25 ℃ of following evacuation, 200Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 7.50g tragacanth, 20.00g microcrystalline Cellulose, 51.62g lactose, mix more than 5 minutes, add the magnesium stearate of 0.40g again, mix more than 1 minute, get mixtures II by the prescription ratio;
D, mixtures II put in the dry granulation machine granulates, remaining magnesium stearate is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
E, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
F, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
Detection method with reference to hardness detection method, the detection method of disintegration and the dissolution of embodiment 1 detects, and testing result is following:
(1) tablet that according to said method prepares, hardness is 3.6kg;
(2) tablet that according to said method prepares, be 4 minutes and 54 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 101%.
Comparative example 1 adopts dry granulation prepared limaprost sheet
The prescription of limaprost sheet is formed:
Limaprost α-CD clathrate 0.08g
Mannitol 4.5g
Trehalose 0.5g
Tragacanth 7.50
Microcrystalline Cellulose 20.00g
Lactose 51.62g
Magnesium stearate 0.80g
Process tablet 85mg/ sheet, process 1000
Method for preparing:
A, the dextran that takes by weighing 4.50g, 0.5g trehalose and 0.08g limaprost γ-CD clathrate, with an amount of water dissolution, lyophilization, the pre-freeze temperature is-35 ℃, 100Pa ,-25 ℃ of following evacuation, 200Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 7.50g tragacanth, 20.00g microcrystalline Cellulose, 51.62g lactose, mix more than 5 minutes, add the magnesium stearate of 0.40g again, mix more than 1 minute, get mixtures II by the prescription ratio;
D, mixtures II and remaining magnesium stearate are added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
E, dried mixtures III is adopted the direct compression process tabletting, put the vacuum drier inner drying;
F, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
Detection method with reference to hardness detection method, the detection method of disintegration and the dissolution of embodiment 1 detects, and testing result is following:
(1) tablet that according to said method prepares, hardness is 4.2kg;
(2) tablet that according to said method prepares, be 2 minutes and 20 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 98%.
Comparative example 2 is according to commercially available prod, Japanese ocean prescription and prepared limaprost sheet
The prescription of limaprost sheet is formed:
Limaprost α-CD clathrate 1g
Dextrin 4021g
Purified Water 37.5g
Dextrin 20g
Lactose 172g
Stearic acid 1g
Process tablet 100mg/ sheet, process 1000
Method for preparing:
Take by weighing 21g dextrin 40, be dissolved in the 37.5g Purified Water, after the cyclodextrin alfadex dissolving of adding 1g Lima, lyophilization is ground into powder; Add 20g dextrin, 172g lactose, the mixing of 1g stearic acid in this powder of 7g, adopt rotary tablet machine, pressure is 800kg/cm
2, process 1000, contain limaprost 5 μ g in every.
Detection method with reference to hardness detection method, the detection method of disintegration and the dissolution of embodiment 1 detects, and testing result is following:
(1) tablet that according to said method prepares, hardness is 4.0kg;
(2) tablet that according to said method prepares, be 6 minutes and 30 seconds its disintegration;
(3) tablet that according to said method prepares, its dissolution is 96%.
The research of the embodiment 7 formulation content uniformitys
Uniformity of dosage units to making tablet in embodiment 1～6 and the comparative example 1～2 is investigated, and the result is as shown in table 1.
The assay method of uniformity of dosage units: get 1 in the tablet that makes, place the 10ml volumetric flask, add the about 5ml of water; Shake well makes dispersion, and ultrasonic about 3 minutes, thin up was to scale; Shake up,, discard 3ml and just filtrate with the membrane filtration of 0.45 μ m; Precision is measured subsequent filtrate 5ml, adds the 1ml inner mark solution, and mixing is as need testing solution.10 parts of operation repetitives.Other gets the about 5mg of limaprost reference substance, and accurate the title decides, and places the 100ml volumetric flask, adds dehydrated alcohol and is diluted to scale; Shake up, precision is measured 1ml, places the 100ml volumetric flask, and thin up is to scale; Shake up, precision is measured 5ml, adds the 1ml inner mark solution, and mixing is as reference substance solution.Need testing solution and reference substance solution are injected hplc determination, and sampling volume 100 μ l calculate every content, should (2005 editions two appendix XE of Chinese Pharmacopoeia) up to specification.
The uniformity of dosage units (%) of the preparation of table 1 embodiment and comparative example preparation relatively
| Sequence number | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
Embodiment 6 | Comparative example 1 | Comparative example 2 |
| 1 | 99.57％ | 104.40％ | 101.20％ | 99.82％ | 101.70％ | 98.36％ | 98.5％ | 97.1％ |
| 2 | 99.64％ | 98.85％ | 100.70％ | 100.90％ | 102.50％ | 99.95％ | 102.0％ | 94.7％ |
| 3 | 102.30％ | 104.20％ | 100.20％ | 100.70％ | 100.90％ | 100.37％ | 88.3％ | 96.5％ |
| 4 | 103.10％ | 104.10％ | 104.30％ | 101.25％ | 100.69％ | 98.65％ | 98.7％ | 93.9％ |
| 5 | 106.60％ | 103.80％ | 102.10％ | 102.70％ | 101.52％ | 99.21％ | 97.3％ | 101.4％ |
| 6 | 99.74％ | 99.24％ | 99.56％ | 101.30％ | 99.83％ | 100.60％ | 98.7％ | 105.2％ |
| 7 | 102.20％ | 101.90％ | 100.90％ | 98.56％ | 102.36％ | 98.99％ | 98.4％ | 109.7％ |
| 8 | 105.40％ | 103.65％ | 101.50％ | 99.78％ | 100.82％ | 101.50％ | 102.5％ | 105.4％ |
| 9 | 99.22％ | 99.34％ | 105.70％ | 102.50％ | 99.56％ | 100.78％ | 97.2％ | 113.9％ |
| 10 | 98.84％ | 99.92％ | 103.86％ | 101.30％ | 101.33％ | 101.20％ | 95.3％ | 103.5％ |
| A | 1.66％ | 1.94％ | 2.00％ | 0.88％ | 1.12％ | 0.04％ | 2.30％ | 2.12％ |
| S | 2.73％ | 2.35％ | 1.98％ | 1.26％ | 0.97％ | 1.10％ | 3.94％ | 6.65％ |
| A+I.80S | 6.58％ | 6.17％ | 5.57％ | 3.15％ | 2.87％ | 2.02％ | 9.39％ | 14.09％ |
Percentage ratio is the percentage ratio of principal agent and labelled amount in the table 1; A representes the absolute value of the difference of labelled amount and average; S representes standard deviation; A+1.8S representes the uniformity of dosage units of tablet.
Can know that by table 1 because the present invention has adopted mannitol and other saccharides to make up as lyophilizing stability protective agent (lyophilizing stabilizing agent) according to certain ratio, wherein mannitol is first-selected lyophilizing skeleton agent; Sorbitol or the pro rata adding of other saccharides, make its can be evenly distributed in granules of main drug inside and outside, thereby stop particulate reunion; Play the stable effect of similar spaces; In the quick-freezing process, principal agent can disperse uniformly and can obtain good preparation outward appearance, through the strictness control of freeze drying process parameter; Compare with well-established law; Improved damp and hot unsettled trace drug solution dispersed uniform property and physical and chemical stability in freeze-dried composition, adopted the preparation technology of dry granulation simultaneously, made the principal agent also can be more even in the distribution of tablet finished product; Overcome in low dose of, the strong active ingredient because the generation of incidents such as the content inhomogeneous individual variation that causes of principal agent, serious adverse reaction, for the raising of the quality of the pharmaceutical preparations has further strengthened assurance.
The research of embodiment 8 preparation stabilities
Carry out severe cruel test (60 ℃ ± 2 ℃, RH75% ± 5%) and accelerated test (40 ℃ ± 2 ℃, RH75% ± 5%) respectively to making tablet in embodiment 1～6 and the comparative example 1～2, investigate stability of formulation, the result is shown in table 2 and 3.
The assay method of stability: the test method in " Chinese Pharmacopoeia two appendix of version in 2005 (XIX C) " of writing according to " chemicals stability study technological guidance principle " and Chinese Pharmacopoeia Commission in " medicine stability test guideline " is got these article simulation listing packing (after aluminum-plastic packaged and medicinal desiccant be encapsulated into Aluminum-plastic composite bag); Place 60 ℃ ± 2 ℃, RH75% ± 5% placement sampling in 0,7,14,21 day continuously respectively; In 40 ℃ ± 2 ℃, RH75% ± 5% climatic chamber; Placed 6 months continuously; Take a sample in 1,2,3, during June, the HPLC method is measured the degraded percentage ratio of principal agent in the preparation, and the result is shown in table 2 and 3.
The severe cruel test (60 ℃ ± 2 ℃, RH75% ± 5%) of the preparation of table 2 embodiment and comparative example preparation
The result relatively
| Time (my god) | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
Embodiment 6 | Comparative example 1 | Comparative example 2 |
| 0 | 0.20％ | 0.15％ | 0.23％ | 0.20％ | 0.18％ | 0.25％ | 0.40％ | 0.70％ |
| 7 | 0.70％ | 0.66％ | 0.72％ | 0.86％ | 0.65％ | 0.90％ | 1.20％ | 2.00％ |
| 14 | 1.30％ | 1.45％ | 1.50％ | 1.27％ | 1.60％ | 1.85％ | 3.20％ | 4.10％ |
| 21 | 2.10％ | 1.90％ | 2.24％ | 2.40％ | 2.42％ | 2.63％ | 4.30％ | 5.70％ |
The accelerated test (40 ℃ ± 2 ℃, RH75% ± 5%) of the preparation of table 3 embodiment and comparative example preparation
The result relatively
| Time (moon) | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
Embodiment 6 | Comparative example 1 | Comparative example 2 |
| 0 | 0.20％ | 0.15％ | 0.23％ | 0.20％ | 0.18％ | 0.25％ | 0.40％ | 0.70％ |
| 1 | 0.45％ | 0.52％ | 0.60％ | 0.33％ | 0.49％ | 0.79％ | 1.37％ | 1.80％ |
| 2 | 1.09％ | 1.22％ | 1.19％ | 0.96％ | 1.13％ | 1.34％ | 2.01％ | 3.53％ |
| 3 | 1.42％ | 1.69％ | 1.50％ | 1.55％ | 1.71％ | 2.01％ | 2.98％ | 3.96％ |
| 6 | 2.00％ | 2.08％ | 2.11％ | 2.31％ | 2.50％ | 2.83％ | 4.00％ | 4.77％ |
Percentage sign is the degraded percentage rate of limaprost cyclodextrin clathrate in table 2, the table 3.Data by table 2 and table 3 can be known; Adopt the limaprost tablet stability of the present invention's preparation good; Solved the physicochemical property utmost point of principal agent problem of unstable own; Severe cruel test and accelerated test result show that the content of the tablet catabolite of the preparation of the present invention before the deadline is lower, avoided the generation of side effect and untoward reaction in the clinical practice.
The stripping release test of embodiment 9 pharmaceutical compositions of the present invention
Tablet to preparation among the embodiment 1～6 carries out stripping release test, and concrete process of the test is carried out with reference to the dissolution determination method among the embodiment 1, and result of the test is as shown in table 4, and the release curve is seen Fig. 1.
The external release test of the pharmaceutical composition of table 4 embodiment 1～6
| Time (minute) | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
Embodiment 6 |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 5 | 35％ | 30％ | 36％ | 37％ | 32％ | 34％ |
| 10 | 67％ | 60％ | 61％ | 69％ | 70％ | 71％ |
| 15 | 88％ | 82％ | 89％ | 86％ | 86％ | 85％ |
| 30 | 98％ | 97％ | 99％ | 96％ | 91％ | 96％ |
| 45 | 98％ | 99％ | 100％ | 100％ | 100％ | 101％ |
Percentage sign is the stripping percentage ratio of limaprost cyclodextrin clathrate in the table 4.But by the limaprost sheet of table 4 and Fig. 1 knowledge capital invention preparation, drug effect is fast, release curve that after this can held stationary, and drug level reaches stable state, can improve intravital bioavailability.
Abovely described the present invention in detail, to those skilled in the art, should be understood that the above-mentioned specific embodiment should not be understood that to limit scope of the present invention with reference to the specific embodiment.Therefore, can make various changes and improvement to embodiment of the present invention without departing from the spirit and scope of the present invention.
Claims (6)
1. pharmaceutical composition that comprises limaprost, based on 85 weight portions, this pharmaceutical composition comprises:
Method for preparing:
A, take by weighing 0.72 weight portion mannitol, 1.78 weight portion sorbitol and 0.17 weight portion limaprost hydroxypropyl-α-CD clathrate; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-40 ℃; 200Pa ,-20 ℃ of following evacuation, 100Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 7.00 weight portion starch slurries, 4.50 weight portion polyvidones, 70.23 weight portion lactose in the prescription ratio; Mix more than 5 minutes; The Pulvis Talci that adds 0.30 weight portion again mixed more than 1 minute, got mixtures II;
C, mixtures II put in the dry granulation machine granulates, remaining Pulvis Talci is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
2. pharmaceutical composition that comprises limaprost, based on 85 weight portions, this pharmaceutical composition comprises:
Method for preparing:
A, the mannitol that takes by weighing 0.70 weight portion, 0.70 weight portion trehalose and 0.0125 weight portion limaprost hydroxypropyl-γ-CD clathrate; With an amount of water dissolution; Lyophilization; The pre-freeze temperature is-30 ℃, 300Pa ,-20 ℃ of following evacuation, and 200Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 4.50 weight portion pectin, 8.00 weight portion carboxymethyl starch sodium, 70.08 weight portion maltose in the prescription ratio; Mix more than 5 minutes; The magnesium stearate that adds 0.50 weight portion was again mixed more than 1 minute, got mixtures II;
C, mixtures II put in the dry granulation machine granulates, remaining magnesium stearate is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
3. pharmaceutical composition that comprises limaprost, based on 85 weight portions, this pharmaceutical composition comprises:
Method for preparing:
A, the mannitol that takes by weighing 0.75 weight portion, 0.25 weight portion sucrose and 0.25 weight portion limaprost-α-CD clathrate; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-20 ℃; 65Pa ,-30 ℃ of following evacuation, 90Pa, 30 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized; Cross 100 mesh sieves; Add 10.00 weight portion hydroxypropyl methylcellulose, 10.00 weight portion low-substituted hydroxypropyl celluloses, 63.25 weight portion sorbitol in the prescription ratio, mix more than 5 minutes, add 0.25 parts by weight of micro silica gel powder again; Mix more than 1 minute, get mixtures II;
C, mixtures II put in the dry granulation machine granulates, remaining micropowder silica gel is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
4. pharmaceutical composition that comprises limaprost, based on 85 weight portions, this pharmaceutical composition comprises:
Method for preparing:
A, the mannitol that takes by weighing 5.83 weight portions, 1.17 weight portion lactose and 0.60 weight portion limaprost carboxymethyl-beta-CD inclusion; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-20 ℃; 350Pa ,-15 ℃ of following evacuation, 400Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 20.00 weight portion arabic gums, 5.00 weight portion crospovidones, 50.90 weight portion glycine soluble dextrins in the prescription ratio; Mix more than 5 minutes; The stearic acid that adds 0.75 weight portion again mixed more than 1 minute, got mixtures II;
C, mixtures II put in the dry granulation machine granulates, remaining stearic acid is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
5. pharmaceutical composition that comprises limaprost, based on 85 weight portions, this pharmaceutical composition comprises:
Method for preparing:
A, the mannitol that takes by weighing 5.68 weight portions, 0.82 weight portion sucrose and 0.30 weight portion limaprost dimethyl-beta-CD inclusion; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-25 ℃; 75Pa ,-20 ℃ of following evacuation, 100Pa, 30 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 15.00 weight portion dextrin, 5.00 weight portion carboxymethyl starch sodium, 57.20 weight portion glucoses in the prescription ratio; Mix more than 5 minutes; The sodium stearyl fumarate that adds 0.50 weight portion again mixed more than 1 minute, got mixtures II;
C, mixtures II put in the dry granulation machine granulates, remaining sodium stearyl fumarate is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
6. pharmaceutical composition that comprises limaprost, based on 85 weight portions, this pharmaceutical composition comprises:
Method for preparing:
A, the mannitol that takes by weighing 4.50 weight portions, 0.5 weight portion trehalose and 0.08 weight portion limaprost γ-CD clathrate; With an amount of water dissolution, lyophilization, the pre-freeze temperature is-35 ℃; 100Pa ,-25 ℃ of following evacuation, 200Pa, 20 ℃ of following dryings make freeze-dried mixture I;
B, freeze-dried mixture I is pulverized, cross 100 mesh sieves, add 7.50 weight portion tragacanths, 20.00 weight portion microcrystalline Cellulose, 51.62 weight portion lactose in the prescription ratio; Mix more than 5 minutes; The magnesium stearate that adds 0.40 weight portion was again mixed more than 1 minute, got mixtures II;
C, mixtures II put in the dry granulation machine granulates, remaining magnesium stearate is added in the granule, mix more than 1 minute, mixtures III, put the vacuum drier inner drying;
D, dried mixtures III is adopted the tablet machine tabletting, put the vacuum drier inner drying;
E, the tablet that makes is carried out aluminum-plastic packaged, together wrap into Aluminum-plastic composite bag with medicinal desiccant again.
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| KR101432244B1 (en) * | 2011-04-27 | 2014-08-27 | 영진약품공업 주식회사 | Pharmaceutical composition of limaprost with improved stability and method for preparing thereof |
| JP4890657B1 (en) * | 2011-06-03 | 2012-03-07 | 小野薬品工業株式会社 | Tablet containing Limaprost and β-cyclodextrin |
| TWI508753B (en) * | 2012-02-03 | 2015-11-21 | Ono Pharmaceutical Co | For the manufacture of beta-cyclodextrin (LIMAPROST) preparations |
| WO2014040457A1 (en) * | 2012-09-13 | 2014-03-20 | 上海源力生物技术有限公司 | Intermediate of limaprost, preparation method thereof and preparation method of limaprost therefrom |
| CN104414984B (en) * | 2013-08-30 | 2019-03-05 | 重庆药友制药有限责任公司 | A kind of stable limaprost pharmaceutical composition and preparation method thereof |
| CN104056273A (en) * | 2014-04-03 | 2014-09-24 | 北京泰德制药股份有限公司 | Application of freeze-dried composition in pharmaceutical preparation process and preparation method of freeze-dried composition |
| CN106667944A (en) * | 2015-11-11 | 2017-05-17 | 北京泰德制药股份有限公司 | Sustained release preparation containing prostaglandin drugs |
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