CN102078300B - Solid preparation of Torasemide liposome - Google Patents
Solid preparation of Torasemide liposome Download PDFInfo
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- CN102078300B CN102078300B CN2011100302455A CN201110030245A CN102078300B CN 102078300 B CN102078300 B CN 102078300B CN 2011100302455 A CN2011100302455 A CN 2011100302455A CN 201110030245 A CN201110030245 A CN 201110030245A CN 102078300 B CN102078300 B CN 102078300B
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Abstract
The invention provides a solid preparation of Torasemide liposome, which is prepared from the following raw materials and auxiliaries in parts by weight: 10 parts of Torasemide, 40 to 100 parts of soybean lecithin, 5 to 40 parts of cholesterin, 4 to 20 parts of sodium glycocholate, 60 to 200 parts of sorbitol and 5 to 20 parts of soyasterol. The solid preparation provided by the invention has high dissolubility, high stability, simple preparation method, high envelope rate, uniform particle size and long remaining time in body, thus the quality of preparation product is enhanced, the bioavailability is raised and the toxic and side effects are reduced.
Description
Technical field
The present invention relates to a kind of lipidosome solid preparation, be specifically related to a kind of torasemide lipidosome solid preparation and method for making thereof, comprise tablet, capsule, granule and dispersible tablet, belong to medical technical field.
Background technology
Torasemide, chemistry N-[[(1-Methylethyl) amino] carbonyl] by name-4-[(3-aminomethyl phenyl) amino]-3-pyridine sulfonamide, molecular formula: C
16H
20N
4O
3S, molecular weight: 348.43, structural formula is:
Torasemide is sulphonyl urine pyridines diuretic, mainly acts on the Heng Lishi ascending thick limb of Henle's loop, suppresses Na
+/ K
+/ 2Cl
-Carrier system makes Na in the urine
+, K
+, Cl
-Increase with the drainage of water but acid-base balance in glomerular filtration rate, RPF or the body is not made significant difference.Be used for the edema patient due to congestive heart failure, renal failure and the kidney disease clinically, also can be used for primary hypertension patient.
Torasemide is water insoluble, and the preparation of listing has tablet, capsule and injection at present, and Chinese patent CN101632665A discloses a kind of torasemide combination of oral medication; Process the taste masking compositions by torasemide and gelatin, mannitol, Aspartane; Process dispersible tablet with other adjuvants again, this patent has been improved the taste of taking of dispersible tablet to a certain extent, but the dissolubility of torasemide is not improved with stability; It is low to cause taking the artifact availability, influences drug effect.Chinese patent CN100372534C discloses a kind of torasemide freeze-drying preparation and preparation method thereof, has increased the dissolubility of torasemide effectively through adding sodium bicarbonate, also has document announcement to increase the dissolubility of torasemide through adding Polyethylene Glycol-400; Process injection; But in torasemide's structure amido link is arranged, it is prepared into facile hydrolysis behind the liquid preparation, causes medicament contg to reduce; Related substance increases, and affects the treatment.
Because there is described separately shortcoming respectively in above-mentioned prior art, torasemide still has improved space as active medicine at aspects such as dissolubility, stability, bioavailability, toxic and side effects.
Liposome (liposomes) is to be proposed by biomembranous models of conduct research such as Britain Banghan nineteen sixty-five the earliest.Discoveries such as Banghan form multilamellar vesicle when phospholipid is dispersed in the water, and each layer is lipid bilayer, are separated by water between each layer.Be made up of the lipid bimolecular this afterwards, inside is called liposome for the closed vesicle of water.
People are through discovering, liposome can be controlled the release of medicine as the carrier of medicine, improves drug targeting property, reduces drug toxicity and side effect, improves curative effect of medication.
If can liposome be processed by torasemide, then be expected to overcome a series of problems that existing Demadex exists, improve the dissolubility and the stability of medicine; Prolong drug retention time in vivo; Permanent performance drug effect improves bioavailability, reduces toxic and side effects; Reduce incidence rate of adverse reaction, improve treatment speed and therapeutic effect.
But, the challenge of preparation liposome is to select suitable liposome constituent and method for making.Because the character of liposome is directly closely related with the composition of liposome like stability, envelop rate, onset time, in vivo circulation time, bioavailability and toxic and side effects etc.; And the composition of liposome with the pharmaceutical properties that will seal directly closely related; Therefore, selecting which type of composition to form the torasemide's liposome with better quality is the problem that needs to be resolved hurrily.
Summary of the invention
The inventor is through research in earnest for a long time; Discovery can be prepared into liposome according to special ratios with torasemide and these six kinds of materials of soybean lecithin, cholesterol, NaGC, sorbitol and soyasterol; Again this liposome preparation is become solid preparation, thereby accomplish the present invention.
Torasemide provided by the invention liposome excellent quality, stability is high, and envelop rate is high, and bioavailability is high, thereby colory lipidosome solid preparation is provided.
The object of the present invention is to provide a kind of torasemide liposome and solid preparation thereof; Through active component torasemide and soybean lecithin, cholesterol, NaGC, sorbitol and soyasterol are prepared into liposome, be mixed and made into lipidosome solid preparation with other pharmaceutic adjuvant again.
Solid preparation dissolubility provided by the invention is high, and stability is high, and method for preparing is simple, and envelop rate is high, and particle diameter is even, and medicine retention time in vivo is long, and bioavailability is high, and toxic and side effects is low.
On the one hand, the present invention provides torasemide's liposome, and its supplementary material by the component that comprises following weight proportion is processed:
10 parts of torasemide
Soybean lecithin 40-100 part
Cholesterol 5-40 part
NaGC 4-20 part
Sorbitol 60-200 part
Soyasterol 5-20 part.
On the other hand, the present invention provides the method for preparing of above-mentioned torasemide liposome, and this method may further comprise the steps:
(1) torasemide, soybean lecithin, cholesterol, NaGC and soyasterol are dissolved in an amount of ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 35-40 ℃ of water bath with thermostatic control, rotary evaporation is removed ethanol, on the bottle wall, forms evenly type membrane of lipoprotein;
(3) sorbitol is soluble in water, slowly pour jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's pro-liposome powder.
On the one hand, the present invention provides torasemide's lipidosome solid preparation again, and it comprises above-mentioned torasemide liposome and pharmaceutically acceptable carrier or excipient.
On the one hand, the present invention provides the method for preparing of torasemide's lipidosome solid preparation again, and this method may further comprise the steps:
(1) torasemide's pro-liposome powder of above-mentioned preparation and other adjuvants such as filler, sweeting agent and disintegrating agent pharmaceutically commonly used are mixed, the mix homogeneously that sieves adds binding agent and prepares soft material, the granulation of sieving, drying, granulate;
(2) dried granule adds lubricant and/or aromatic, mix homogeneously;
(3) tabletting or packing make torasemide's lipidosome solid preparation.
Torasemide provided by the invention lipidosome solid preparation and preparation method thereof, advantage shows the following aspects:
(1) through liposome torasemide is wrapped up, improved the dissolubility of torasemide greatly, improved the bioavailability after oral;
(2) through liposome torasemide is wrapped up, improved the stability of torasemide, ensured clinical efficacy;
(3) the liposome preparation process is simple, and envelop rate is high, and yield is high, is suitable for suitability for industrialized production;
(4) improve the formulation products quality, reduced toxic and side effects.
The specific embodiment
Describe the present invention below in conjunction with the specific embodiment.Characteristics of the present invention and advantage can become more clear along with these descriptions.
On the one hand, the present invention provides torasemide's liposome, and its supplementary material by the component that comprises following weight proportion is processed:
10 parts of torasemide
Soybean lecithin 40-100 part
Cholesterol 5-40 part
NaGC 4-20 part
Sorbitol 60-200 part
Soyasterol 5-20 part.
In an embodiment of torasemide of the present invention liposome, used supplementary material preferably includes the component of following weight proportion:
10 parts of torasemide
Soybean lecithin 60-80 part
Cholesterol 10-20 part
NaGC 10-20 part
Sorbitol 80-150 part
Soyasterol 6-10 part.
Used supplementary material more preferably comprises the component of following weight proportion:
10 parts of torasemide
80 parts of soybean lecithins
10 parts in cholesterol
15 parts of NaGCs
80 parts of sorbitol
8 parts of soyasterols.
In further preferred embodiment, used supplementary material is made up of the component of above-mentioned weight proportion.
In torasemide of the present invention liposome, the phospholipid material that uses is soybean lecithin (Lecithin High Potency is also referred to as the Semen sojae atricolor lecithin, is a kind of natural phospholipid).
The phospholipid material commonly used that is used to form is of a great variety, comprises soybean lecithin, lecithin, Ovum Gallus domesticus Flavus lecithin, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean phospholipid acyl glycerol, soy phosphatidylserine, soybean phospholipid acyl inositol, two Laurel phosphatidyl cholines, two myristoyl phosphatidyl phatidylcholines, dipalmitoyl phosphatidyl choline, DSPC, myristoyl phosphatidylcholine, palmityl myristoyl phosphatidylcholine, palmityl stearoyl phosphatidylcholine, stearoyl palmitoylphosphatidyl choline, dioleoyl phospholipid phatidylcholine, two lauroyl phosphatidyl glycerols, two myristoyl phosphatidyl acyl glycerol, two palmityl phosphatidyl glycerols, distearyl phosphatidyl glycerol, DOPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, DOPG, two myristoyl phosphatidic acid, two palmityl phosphatidic acid, two palmityl PHOSPHATIDYL ETHANOLAMINEs, two palmityl PHOSPHATIDYL ETHANOLAMINEs, two myristoyl Phosphatidylserine and two palmityl Phosphatidylserine etc.
The inventor is through discover with keen determination; In common phospholipid material; The soybean lecithin of appropriate amount can be used to form colory torasemide liposome, can form the liposome of dissolubility and excellent in stability through the method that provides among the present invention, and the size of liposome suitably, constituent is suitable, envelop rate is high; And these compositions, especially non-leakage in formed liposome as the torasemide of active component.A large amount of result of the tests show, select other phospholipid material for use, can't form the good liposome of quality.
In the torasemide of the present invention liposome; Based on 10 weight portion torasemide; If the amount of soybean lecithin is lower than 40 weight portions, then can't form stabilized liposomes, if the amount of soybean lecithin is higher than 100 weight portions; Then the envelop rate of torasemide reduces, and the stability of liposome descends to some extent.
In the torasemide of the present invention liposome, the membrane structure of cholesterol regulation liposome is regulated the flowability and the permeability of membrane structure.Based on 10 weight portion torasemide, the cholesterol of 5-40 weight portion can form the liposome that has good stability.
In torasemide of the present invention liposome, NaGC plays increases liposome dissolving property and the effect that further strengthens the stability of liposome.Based on 10 weight portion torasemide, the NaGC of 4-20 weight portion can form the liposome that has good stability.
In torasemide of the present invention liposome, sorbitol plays increases liposome dissolving property and the effect that further strengthens the stability of liposome.Based on 10 weight portion torasemide, 60-200 weight portion sorbitol can form dissolubility and the liposome that has good stability.
In torasemide of the present invention liposome, soyasterol further strengthens the stability of liposome.Based on 10 weight portion torasemide, 5-20 weight portion soyasterol can form the liposome that has good stability.
Said soyasterol is the hydrolyzate that the soyasterol glucoside removes glucose residue; And the soyasterol glucoside is the mixture from the sterol glucoside of through the Semen sojae atricolor residue that refines Oleum Glycines, separating, and is the product of natural origin, and is safe; Be easy to obtain, and low price.
The inventor finds unexpectedly; The cholesterol of above-mentioned specified weight proportioning, NaGC, sorbitol and soyasterol can be worked in coordination with the film-formation result that promotes soybean lecithin; Make the dissolubility and the stability of formed torasemide liposome significantly improve; And formed torasemide lipid granule size is suitable, particle size distribution is even, and envelop rate is high, and toxic and side effects is low.
On the other hand, the present invention provides the method for preparing of above-mentioned torasemide liposome, and this method may further comprise the steps:
(1) torasemide, soybean lecithin, cholesterol, NaGC and soyasterol are dissolved in an amount of ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 35-40 ℃ of water bath with thermostatic control, rotary evaporation is removed ethanol, on the bottle wall, forms evenly type membrane of lipoprotein;
(3) sorbitol is soluble in water, slowly pour jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's pro-liposome powder.
Torasemide's liposome dissolving property through method preparation provided by the invention is high, and stability is high, and powder diameter is little, particle size distribution is even, and envelop rate is high.And this method technology is simple, is convenient to suitability for industrialized production.
On the one hand, the present invention provides torasemide's lipidosome solid preparation again, and it comprises above-mentioned torasemide liposome and pharmaceutically acceptable carrier or excipient.
Torasemide provided by the present invention lipidosome solid preparation comprises oral formulations such as tablet, capsule, granule and dispersible tablet.
According to torasemide's lipidosome solid preparation dosage form of hope, can select appropriate carriers or excipient and amount thereof.
For example, in torasemide of the present invention lipidosome solid preparation, used pharmaceutically acceptable carrier or excipient (also being referred to as adjuvant sometimes) comprise filler, sweeting agent, disintegrating agent, binding agent, lubricant, aromatic and coloring agent etc.The amount ranges of various carriers or excipient is the conventional amount used scope of general solid preparation; There are not specific (special) requirements and regulation; Can be selected according to various carriers or the general consumption of excipient in solid preparation by those skilled in the art, this is in those skilled in the art's limit of power.
As preferably, filler can be selected from one or more in starch, lactose, microcrystalline Cellulose, pregelatinized Starch, the dextrin, is preferably lactose and starch.
As preferably, sweeting agent is selected from one or more in sucrose, mannitol, sorbitol, xylitol, Aspartane, stevioside, saccharin sodium, the sucralose, is preferably sucrose and stevioside.
As preferably, disintegrating agent is selected from one or more in low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, the carboxymethylcellulose calcium, is preferably carboxymethylstach sodium.
As preferably, binding agent is selected from a kind of in 30 POVIDONE K 30 BP/USP 30, starch slurry, hypromellose, sodium carboxymethyl cellulose, arabic gum, the xanthan gum, is preferably 30 POVIDONE K 30 BP/USP 30.
As preferably, lubricant is selected from one or more among magnesium stearate, zinc stearate, Pulvis Talci, micropowder silica gel, the PEG6000, is preferably magnesium stearate.
As preferably, aromatic is selected from a kind of in flavoring orange essence, strawberry essence, chocolate essence, the apple essence, is preferably strawberry essence.
As preferably, coloring agent is selected from sunset yellow.
In practice, consider the effective dose of medicine and the convenience of medication, in the preferred embodiment of torasemide of the present invention lipidosome solid preparation, the specification dosage of torasemide is 2.5mg or 5.0mg.
On the one hand, the present invention provides the method for preparing of torasemide's lipidosome solid preparation again, and this method may further comprise the steps:
(1) the torasemide's pro-liposome powder with above-mentioned preparation mixes with filler, sweeting agent and disintegrating agent, and the mix homogeneously that sieves adds binding agent and prepares soft material, the granulation of sieving, drying, granulate;
(2) dried granule adds lubricant and/or aromatic, mix homogeneously;
(3) tabletting or packing make torasemide's lipidosome solid preparation.
In a preferred implementation of the method for preparing of torasemide provided by the invention lipidosome solid preparation, in step (1), as the ethanol water of binding agent, working concentration is the ethanol water of 20%-80% (w/w).
In a preferred implementation of the method for preparing of torasemide provided by the invention lipidosome solid preparation; In step (1), 60 mesh sieve mix homogeneously are crossed with other adjuvant by torasemide, cross 20-30 mesh sieve system wet granular behind the system soft material; 50-60 ℃ of drying, 18 mesh sieve granulate.
In the method for the invention, can also sterilize to liposome and/or lipidosome solid preparation as required.Sterilizing methods does not have specific (special) requirements, can use liposome sterilizing methods commonly used in the pharmaceutical field, like heat sterilization, filtration sterilization, radiation sterilization or sterile working etc.
The present invention is prepared into liposome through the specific combined of active component torasemide and soybean lecithin, cholesterol, NaGC, sorbitol and soyasterol earlier, is mixed and made into solid preparation with other pharmaceutic adjuvant again.Gained solid preparation excellent in stability, particle diameter is even, and envelop rate is high, and the dissolubility in water is big, and medicine retention time in blood circulation is long, and is evident in efficacy; Used adjuvant cheap and simple, availability is high, pollutes little, the economic worth height.The method for preparing of torasemide provided by the invention lipidosome solid preparation has improved product quality, has reduced toxic and side effects, and the equipment of method for preparing is simple, easy operating, and industrialized great production is highly advantageous to.
In this article; If not explanation especially; Content or consumption are all in weight portion; The device that is adopted, instrument, raw material, material, consumption, method, time, appropriateness and other conditions all are well-known in the art, or those skilled in the art combine prior art to obtain according to the description of applying for.
Embodiment
Below further specify the present invention through embodiment, but the present invention is not limited to the method for preparing of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
The preparation of embodiment 1 torasemide's liposome tablet
Used supplementary material is following:
The 5g of torasemide
Soybean lecithin 40g
Cholesterol 5g
NaGC 7.5g
Sorbitol 40g
Soyasterol 4g
Lactose 50g
Starch 65g
Carboxymethylstach sodium 10g
30 POVIDONE K 30 BP/USP 30 10g
Magnesium stearate 4g
Preparation technology:
(1) 5g torasemide, 40g soybean lecithin, 5g cholesterol, 7.5g NaGC and 4g soyasterol are dissolved in the 800ml ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 40 ℃ of waters bath with thermostatic control, rotary evaporation is removed ethanol, forms evenly type membrane of lipoprotein on the bottle wall;
(3) the 40g sorbitol is dissolved in the 400ml water, slowly pours jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's pro-liposome powder;
(5) torasemide's pro-liposome powder and 50g lactose, 65g starch, the 10g carboxymethylstach sodium with above-mentioned preparation mixes; Cross 60 mesh sieve mix homogeneously, 20% alcoholic solution that adds 5% 30 POVIDONE K 30 BP/USP 30 prepares soft material, crosses 20 mesh sieves and granulates; 50 ℃ of dryings, 18 order granulate;
(6) dried granule adds 4g magnesium stearate, mix homogeneously;
(7) tabletting makes 1000 torasemide's liposome tablets.
The preparation of embodiment 2 torasemide's liposome tablets
Used supplementary material is following:
The 2.5g of torasemide
Soybean lecithin 12g
Cholesterol 5g
NaGC 4g
Sorbitol 20g
Soyasterol 1.5g
Lactose 26g
Starch 32g
Carboxymethylstach sodium 5g
30 POVIDONE K 30 BP/USP 30 5g
Magnesium stearate 2g
Preparation technology:
(1) 2.5g torasemide, 12g soybean lecithin, 5g cholesterol, 4g NaGC and 1.5g soyasterol are dissolved in the 400ml ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 40 ℃ of waters bath with thermostatic control, and rotary evaporation is removed ethanol, the even type membrane of lipoprotein of formation on the bottle wall;
(3) the 20g sorbitol is dissolved in the 200ml water, slowly pours jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's pro-liposome powder;
(5) torasemide's pro-liposome powder and 26g lactose, 32g starch, the 5g carboxymethylstach sodium with above-mentioned preparation mixes; Cross 60 mesh sieve mix homogeneously, 20% alcoholic solution that adds 5% 30 POVIDONE K 30 BP/USP 30 prepares soft material, crosses 20 mesh sieves and granulates; 50 ℃ of dryings, 18 order granulate;
(6) dried granule adds 2g magnesium stearate, mix homogeneously;
(7) tabletting makes 1000 torasemide's liposome tablets.
The preparation of embodiment 3 torasemide's liposome dispersible tablets
Used supplementary material is following:
The 5g of torasemide
Soybean lecithin 30g
Cholesterol 2.5g
NaGC 2g
Sorbitol 30g
Soyasterol 10g
Mannitol 40g
Starch 30g
Polyvinylpolypyrrolidone 10g
Stevioside 5g
Hypromellose 3g
Pulvis Talci 10g
Preparation technology
(1) 5g torasemide, 30g soybean lecithin, 2.5g cholesterol, 2g NaGC and 10g soyasterol are dissolved in the 600ml ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 60 ℃ of waters bath with thermostatic control, and rotary evaporation is removed ethanol, the even type membrane of lipoprotein of formation on the bottle wall;
(3) the 30g sorbitol is dissolved in the 120ml water, slowly pours jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's pro-liposome powder;
(5) torasemide's pro-liposome powder and 40g mannitol, 30g starch, 10g polyvinylpolypyrrolidone, the 5g stevioside with above-mentioned preparation mixes; Cross 60 mesh sieve mix homogeneously; 50% alcoholic solution that adds 2% hypromellose prepares soft material; Cross 30 mesh sieves and granulate 60 ℃ of dryings, 18 order granulate;
(6) dried granule adds 10g Pulvis Talci, mix homogeneously;
(7) tabletting makes 1000 torasemide's liposome dispersible tablets.
The preparation of embodiment 4 torasemide's lipidosome capsules
Used supplementary material is following:
The 10g of torasemide
Soybean lecithin 50g
Cholesterol 30g
NaGC 12g
Sorbitol 100g
Soyasterol 7g
Pregelatinized Starch 120g
Micropowder silica gel 10g
Preparation technology:
(1) 10g torasemide, 50g soybean lecithin, 30g cholesterol, 12g NaGC and 7g soyasterol are dissolved in the 700ml ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 55 ℃ of waters bath with thermostatic control, and rotary evaporation is removed ethanol, the even type membrane of lipoprotein of formation on the bottle wall;
(3) the 100g sorbitol is dissolved in the 400ml water, slowly pours jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's pro-liposome powder;
(5) torasemide's pro-liposome powder and 120g pregelatinized Starch, the 10g micropowder silica gel with above-mentioned preparation mixes, and crosses 60 mesh sieve mix homogeneously;
(6) filled capsules makes 2000 torasemide's lipidosome capsules.
The preparation of embodiment 5 torasemide liposome particles agent
Used supplementary material is following:
The 10g of torasemide
Soybean lecithin 100g
Cholesterol 40g
NaGC 4g
Sorbitol 200g
Soyasterol 20g
Sucrose 300g
Aspartane 15g
Flavoring orange essence 25g
30 POVIDONE K 30 BP/USP 30 7.5g
Sunset yellow 0.5g
Preparation technology
(1) 10g torasemide, 100g soybean lecithin, 40g cholesterol, 4g NaGC and 20g soyasterol are dissolved in the 1500ml ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 60 ℃ of waters bath with thermostatic control, and rotary evaporation is removed ethanol, the even type membrane of lipoprotein of formation on the bottle wall;
(3) the 200g sorbitol is dissolved in the 800ml water, slowly pours jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's pro-liposome powder;
(5) torasemide's pro-liposome powder and 400g sucrose, the 15g Aspartane of above-mentioned preparation are mixed; Cross 60 mesh sieve mix homogeneously; 80% alcoholic solution that adds 5% 30 POVIDONE K 30 BP/USP 30 that contains 0.5g sunset yellow and 25g flavoring orange essence prepares soft material; Cross 24 mesh sieves and granulate 55 ℃ of dryings, 18 order granulate;
(6) pack makes 2000 bags of torasemide's liposome particles agent.
The preparation of Comparative Examples 1 torasemide's liposome tablet
Used supplementary material is following:
The 5g of torasemide
Soybean lecithin 20g
Cholesterol 2g
NaGC 7.5g
Sorbitol 40g
Soyasterol 4g
Lactose 50g
Starch 65g
Carboxymethylstach sodium 10g
30 POVIDONE K 30 BP/USP 30 10g
Magnesium stearate 4g
Preparation technology is identical with embodiment 1, makes 1000 torasemide's liposome tablets.
The preparation of Comparative Examples 2 torasemide's liposome tablets
Used supplementary material is following:
The 5g of torasemide
Soybean lecithin 40g
Cholesterol 5g
NaGC 7.5g
Sorbitol 40g
Lactose 50g
Starch 65g
Carboxymethylstach sodium 10g
30 POVIDONE K 30 BP/USP 30 10g
Magnesium stearate 4g
Preparation technology is identical with embodiment 1, makes 1000 torasemide's liposome tablets.
The preparation of Comparative Examples 3 torasemide's liposome tablets
Used supplementary material is following:
The 5g of torasemide
Soybean lecithin 40g
Cholesterol 5g
Sorbitol 40g
Soyasterol 4g
Lactose 50g
Starch 65g
Carboxymethylstach sodium 10g
30 POVIDONE K 30 BP/USP 30 10g
Magnesium stearate 4g
Preparation technology is identical with embodiment 1, makes 1000 torasemide's liposome tablets.
The preparation of Comparative Examples 4 torasemide's liposome tablets
Identical among used supplementary material and the embodiment 1, preparation technology is following:
(1) soybean lecithin, cholesterol, NaGC and soyasterol are dissolved in the 300ml isopropyl alcohol, get a type lipoprotein solution;
(2) torasemide and sorbitol are dissolved in the 200ml water, above-mentioned type of lipoprotein solution splashed into wherein at leisure, even with magnetic stirrer simultaneously, mixing time is 90min, obtains containing the liposome turbid liquor of isopropyl alcohol;
(3) place ultrasonic container ultrasonic above-mentioned suspension to translucent colloid solution;
(4) above-mentioned translucent colloid being used the aperture is 0.45 μ m filtering with microporous membrane; Filtrating placed under-30 ℃ of conditions pre-freeze 6 hours; Slowly be warming up to-6 ℃ with 4 ℃/hour speed then, be incubated 2 hours, be warming up to 30 ℃ with 6 ℃/hour speed again; Heat preservation and dryness 4 hours obtains torasemide's pro-liposome lyophilized powder;
(5) torasemide's pro-liposome powder and 50g lactose, 65g starch, the 10g carboxymethylstach sodium with above-mentioned preparation mixes; Cross 60 mesh sieve mix homogeneously, 20% alcoholic solution that adds 5% 30 POVIDONE K 30 BP/USP 30 prepares soft material, crosses 20 mesh sieves and granulates; 50 ℃ of dryings, 18 order granulate;
(6) dried granule adds 4g magnesium stearate, mix homogeneously;
(7) tabletting makes 1000 torasemide's liposome tablets.
The mensuration of Test Example 1 liposome encapsulation
Adopt ultracentrifugal method to measure the envelop rate of torasemide's liposome, the concrete operations step is following:
(1) preparation of centrifugal sample solution: precision is measured the liposome turbid liquor 10ml of torasemide that makes among embodiment 1-5 and the Comparative Examples 1-4, places freezing ultra-lowing centrifuge, 13000r/min, 4 ℃ of centrifugal 30min.Get supernatant, be used for the free content of medicines of liposome solutions and measure.
(2) the not preparation of centrifuged sample solution: precision is measured the liposome turbid liquor 10ml of torasemide that makes among embodiment 1-5 and the Comparative Examples 1-4; Place the brown volumetric flask of 25ml; The alcoholic solution 10ml breakdown of emulsion of the Triton X-100 of adding 5%; With distilled water diluting and be settled to scale, shake up, be used for the total content of medicines of liposome and measure.
(3) get the centrifugal sample solution of gained torasemide liposome in above-mentioned (1) and the not centrifugal sample solution of above-mentioned (2) middle gained torasemide liposome respectively; Measure peak area by corresponding chromatographic condition, and calculate the centrifugal sample solution Chinese medicine concentration (C of torasemide's liposome
Free) and the not centrifugal sample solution Chinese medicine concentration (C of torasemide's liposome
Always), multiply by separately more respectively, extension rate promptly gets the not weight (W of entrapped drug
Free) and the gross weight (W of liposome Chinese medicine
Always), through the computes envelop rate, envelop rate=(W
Always-W
Free)/W
Always* 100%.
Respectively the pro-liposome freeze-dried powder of embodiment 1-5 and Comparative Examples 1-4 is measured envelop rate, shown in result such as the following table 1.
The envelop rate of table 1 liposome
Can know that by table 1 compare with the liposome of 1-4 in the Comparative Examples, the envelop rate of torasemide of the present invention liposome will exceed a lot.
Especially, can know that through comparing embodiment 1-5 and the Comparative Examples 2-3 that lacks the composition in the scope of the invention liposome of the present invention has higher envelop rate.This shows that the envelop rate of torasemide's liposome is relevant with the composition kind that is used to form liposome.
Especially, through comparing embodiment 1-5 and weight proportion not within the scope of the present invention Comparative Examples 1 can know that liposome of the present invention has higher envelop rate.This shows that the envelop rate of torasemide's liposome is not only relevant with the composition that is used to form liposome, and is also directly related with the consumption of each composition.
Can know that through comparing embodiment 1 and Comparative Examples 4 when using same supplementary material, the envelop rate of the liposome that makes through the inventive method is higher.
The mensuration of Test Example 2 liposome particle diameters
With among electron microscope observation embodiment 1-5 and the Comparative Examples 1-4 in the particle diameter of torasemide's pro-liposome freeze-dried powder that step (4) makes, shown in result such as the following table 2.
The particle diameter of table 2 liposome
Can know that by table 2 mean diameter of gained liposome is little more a lot of than the mean diameter of gained liposome among the Comparative Examples 1-4 among the embodiment of the invention 1-5, and the size homogeneous.
Especially, can know that though that both are used to form the raw material of liposome is identical, under the situation of different method for preparinies, the liposome that forms through the inventive method has littler particle diameter, particle size distribution more uniformly through comparing embodiment and Comparative Examples 4.
Existing research shows, liposome particles size and the degree of being evenly distributed and its stability and envelop rate and relevant in the intravital time of staying of people, and liposome particles is more little, particle size distribution is even more; Its stability and envelop rate high more, the time of staying in the human recycle system longer (referring to novel pharmaceutical formulation, front page; The 18 chapter; The 408-468 page or leaf, Zhu Shengshan chief editor, Chemical Industry Press).The document is introduced here as a reference in full.
Therefore, little, the particle size distribution of torasemide of the present invention liposome mean diameter evenly is a factor that further promotes excellent performances such as its stability, envelop rate, retention time time length in vivo, bioavailability.
The stability study of Test Example 3 liposomees
Through accelerated test, the stability of the torasemide's lipidosome solid preparation among evaluation embodiment of the invention 1-5 and the Comparative Examples 1-4 and commercially available torasemide's tablet (Hubei encyclopaedia Heng Di pharmaceutcal corporation, Ltd produces, lot number 20100306-2).Under 40 ℃ temperature, relative humidity 75% ± 5% condition was carried out accelerated test in following 6 months, and the result is as shown in table 3 below.
Table 3 accelerated test result
Can know that by table 3 stability of torasemide's lipidosome solid preparation of embodiment of the invention 1-5 is higher than torasemide's lipidosome solid preparation of Comparative Examples 1-4 and commercially available torasemide's tablet.
Claims (9)
1. torasemide's liposome is characterized in that, the method preparation of this torasemide's liposome through may further comprise the steps:
(1) torasemide, soybean lecithin, cholesterol, NaGC and soyasterol are dissolved in an amount of ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 35-40 ℃ of water bath with thermostatic control, rotary evaporation is removed ethanol, on the bottle wall, forms evenly type membrane of lipoprotein;
(3) sorbitol is soluble in water, slowly pour jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's liposome powder;
Wherein by weight ratio:
2. torasemide according to claim 1 liposome is characterized in that, wherein by weight ratio:
3. the method for preparing of claim 1 or 2 described torasemide liposomees, this method may further comprise the steps:
(1) torasemide, soybean lecithin, cholesterol, NaGC and soyasterol are dissolved in an amount of ethanol, get a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed flask, in 35-40 ℃ of water bath with thermostatic control, rotary evaporation is removed ethanol, on the bottle wall, forms evenly type membrane of lipoprotein;
(3) sorbitol is soluble in water, slowly pour jog in the flask into, type of making membrane of lipoprotein eluting also is distributed to the hydration medium dissolving, promptly gets liposome turbid liquor;
(4) above-mentioned suspension being used the aperture is 0.45 μ m filtering with microporous membrane, and spray drying obtains torasemide's liposome powder.
4. torasemide's lipidosome solid preparation; It comprises claim 1 or 2 described torasemide liposomees and pharmaceutically acceptable carrier or excipient, and said carrier or excipient comprise filler, sweeting agent, disintegrating agent, binding agent, lubricant, aromatic and coloring agent.
5. torasemide according to claim 4 lipidosome solid preparation, it is tablet, capsule or granule.
6. torasemide according to claim 5 lipidosome solid preparation, it is a chewable tablet.
7. the method for preparing of torasemide's lipidosome solid preparation, this method comprises:
(1) with claim 1 or 2 described torasemide liposome powder and filler, sweeting agent and disintegrating agent mixing pharmaceutically commonly used, the mix homogeneously that sieves adds binding agent and prepares soft material, the granulation of sieving, drying, granulate;
(2) the dried granule of gained adds lubricant and/or aromatic, mix homogeneously;
(3) tabletting or packing make torasemide's lipidosome solid preparation.
8. method for preparing according to claim 7 is characterized in that, in step (1), binding agent is that concentration is the ethanol water of 20%-80% (w/w).
9. according to claim 7 or 8 each described method for preparinies, it is characterized in that, in step (1); Torasemide's liposome powder and filler, sweeting agent and disintegrating agent are crossed 60 mesh sieve mix homogeneously; Cross 20-30 mesh sieve system wet granular behind the system soft material, 50-60 ℃ of drying, 18 mesh sieve granulate.
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