CN102327269B - Solid lipidosome preparation of compound cefaclor medicinal composition - Google Patents
Solid lipidosome preparation of compound cefaclor medicinal composition Download PDFInfo
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- CN102327269B CN102327269B CN201110196522XA CN201110196522A CN102327269B CN 102327269 B CN102327269 B CN 102327269B CN 201110196522X A CN201110196522X A CN 201110196522XA CN 201110196522 A CN201110196522 A CN 201110196522A CN 102327269 B CN102327269 B CN 102327269B
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Abstract
The invention discloses a solid lipidosome preparation of a compound cefaclor medicinal composition and a preparation method thereof. A compound cefaclor medicinal composition lipidosome with excellent quality can be formed by selecting cefaclor, bromhexine, dimyristoylphosphatidylcholine, cholesterol and tween 20 in a specific weight proportion; and the lipidosome is prepared into the solid preparation by adopting a general preparation method. Compared with the prior art, the preparation disclosed by the invention has the advantages of greatly-improved quality of a preparation product, reduced toxic or side effects, high bioavailability, stable medicament release and more remarkable curative effect.
Description
Technical field
The present invention relates to a kind of antibiotic Liposomal formulation, be specifically related to a kind of compound cefaclor medicine compound liposome solid preparation, belong to medical technical field.
Background technology
The pharmaceutical composition that cefaclor is made up of strong effect oral cephalo-type antimicrobial drug cefaclor and a kind of strong effect antisussive and expectorant agent Bisolvon.These two kinds of ingredient couplings produce synergism, are used to treat respiratory tract infection, simultaneously with diseases such as cough ant phlegms, have infection, cough-relieving, a double effects that eliminates the phlegm, and can alleviate rapidly, cure the respiratory tract infection symptom, be a kind of therapeutic effect excellent drug.
Cefaclor (Cefaclor), chemical name be (6R, 7R)-7-[(R)-2-amino-2-phenylacetylamino]-3-chloro-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid hydrate, molecular formula C
15H
14ClN
3O
4SH
2O, molecular weight 385.82, structural formula is following:
Cefaclor is the semisynthetic cephalosporins of wide spectrum, through suppressing the germ-resistant effect of playing of synthesizing of cell wall.Cefaclor all has very strong bactericidal action to multiple gram positive bacteria and gram negative bacteria; Activity to producing penicillinase staphylococcus aureus, A group Hemolytic streptococcus, Streptococcus viridans and staphylococcus epidermidis is identical with cefadroxil; Strong 2～4 times to not producing enzyme staphylococcus aureus and pneumococcal antibacterial action than cefadroxil; Gram negative bacilli is comprised the activity of escherichia coli and Klebsiella Pneumoniae etc. strong than cefalexin, similar with cefadroxil; Activity to proteus mirabilis, Salmonella and Shigella is strong than cefadroxil; 2.9 these article of～8mg/L can suppress all hemophilus influenzas, comprise the drug-fast bacterial strain in ampicillin.
Bromhexine (bromhexine), chemical name are N-(2-amino-3,5-dibromo-benzyl)-N-cyclohexyl methylamine hydrochloride, molecular formula C
14H
20BrN
2HCl, molecular weight 412.60, structural formula is following:
Bisolvon is a kind of expectorant, can directly act on the bronchus body of gland, impels mucous secretion, and the viscosity of expectorant is reduced, and sputum is thinning and be easy to expectoration.
The preparation of compound cefaclor pharmaceutical composition mainly is dosage forms such as capsule, dry suspension, Film coated tablets, dispersible tablet, granule at present.Because the water solublity of cefaclor and bromhexine is all very poor, and medicine stripping from preparation, absorption need the regular hour, cause the drug effect trials and tribulations.
In addition, the long-term less stable of placing of the preparation of existing compound cefaclor pharmaceutical composition.
For example, one Chinese patent application CN1666743A discloses a kind of compound cefaclor dispersible tablet and preparation method thereof, and it comprises cefaclor, Bisolvon, filler, diluent, disintegrating agent, lubricant.Though this dispersible tablet disintegrate is rapid, dissolution improves, and drug absorption speed, onset time and bioavailability obtain improvement to a certain degree, but its long-term stability of placing and bioavailability remain further to be improved.
One Chinese patent application CN101836994A discloses a kind of cefaclor and bromhexine compound oral administration preparation and preparation method thereof, and said preparation comprises cefaclor, bromhexine, filler, diluent, disintegrating agent and lubricant.Same stability and the low problem of bioavailability that has long-term placement of said preparation.
One Chinese patent application CN101912368A discloses a kind of compound recipe clo dry suspension and preparation method thereof, and it comprises cefaclor, Bisolvon, the agent of macromolecule suspending, sweeting agent, sucrose, sunset yellow, Fructus Citri tangerinae essence.Though said preparation makes moderate progress to stability, but long-term stability of placing still has the space of further raising.In addition, bioavailability also has much room for improvement.
Because there is described separately shortcoming respectively in above-mentioned prior art, the compound cefaclor pharmaceutical composition still has improved space as active medicine at aspects such as dissolubility, stability, bioavailability.
Liposome is meant drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms, and belongs to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine like liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can protect the medicine that is wrapped effectively, improve bioavailability; Change medicine distribution in vivo, and can the release of targeting property, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
The main mechanism of action of conventional liposome is that drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome bilayer lipid membrane; This microgranule type of having cellularity; Get into the interior principal agent of human body is activated body by reticuloendothelial system phagocytic autoimmune function; And change is distributed in the body of entrapped drug; Drug main to be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the therapeutic dose and the toxicity that reduces medicine of medicine.
If can the compound cefaclor pharmaceutical composition be processed liposome; Then be expected to overcome a series of problems that existing compound cefaclor drug combination preparation exists; Improve the dissolubility and the stability of medicine, prolong drug retention time in vivo improves bioavailability; Reduce toxic and side effects, 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 discover with keen determination; Through cefaclor, bromhexine, dimyristoyl phosphatidyl choline, cholesterol and the polysorbas20 of selecting the specified weight proportioning for use; Can form the compound cefaclor medicine compound liposome of excellent quality; Again liposome is processed solid preparation with general formulation method, thereby accomplish the present invention.
The purpose of this invention is to provide a kind of compound cefaclor medicine compound liposome, it is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1: 2-1: 4.
Another object of the present invention provides the method for preparing of above-mentioned compound cefaclor medicine compound liposome, and this method may further comprise the steps:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, concussion is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid.
A purpose more of the present invention provides a kind of compound cefaclor medicine compound liposome solid preparation, and it is processed by compound cefaclor medicine compound liposome and other pharmaceutic adjuvants,
Wherein said compound cefaclor medicine compound liposome is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1: 2-1: 4;
Based on the cefaclor of 250 weight portions, the amount of other pharmaceutic adjuvants is 100-500 part.
A purpose more of the present invention provides the method for preparing of above-mentioned compound cefaclor medicine compound liposome solid preparation, and this method may further comprise the steps:
(1) preparation of compound cefaclor medicine compound liposome: cefaclor, bromhexine, dimyristoyl phosphatidyl choline, cholesterol and polysorbas20 are mixed and made into lipidosome solid;
(2) preparation of compound cefaclor medicine compound liposome solid preparation: compound cefaclor medicine compound liposome and other pharmaceutic adjuvants are mixed with the compound cefaclor medicine compound liposome solid preparation, and wherein said pharmaceutic adjuvant is selected from filler, disintegrating agent, sweeting agent, lubricant and combination thereof.
Wherein, the preparation of step (1) compound cefaclor pharmaceutical composition plastid comprises following substep:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, concussion is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid.
The preparation of step (2) compound cefaclor medicine compound liposome solid preparation comprises following substep:
(d) compound cefaclor medicine compound liposome solid and filler, disintegrating agent, sweeting agent are mixed, the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, drying;
(e) dried granule and mix lubricant is even, the granulate that sieves, tabletting, filled capsules or pack make the compound cefaclor medicine compound liposome solid preparation.
Compare with existing preparation technique, compound cefaclor medicine compound liposome solid preparation provided by the invention has improved stability of formulation and bioavailability greatly; Reduce toxic and side effects, improved the formulation products quality, improved therapeutic effect.
Description of drawings
Fig. 1 is the cefaclor release profiles of preparation.
Fig. 2 is the bromhexine release profiles of preparation.
The specific embodiment
Below further specify through specific embodiment the present invention, characteristics of the present invention and advantage will become more clear along with these explanations.
In order to form colory compound cefaclor medicine compound liposome solid preparation; Can good compatible with the compound cefaclor pharmaceutical composition it well be sealed and non-leakage filmogen thereby importantly seek; So that form colory compound cefaclor medicine compound liposome, and seek the pharmaceutic adjuvant that can form solid preparation with the compound cefaclor medicine compound liposome.
To achieve these goals; Big quantity research and realization that the inventor carries out; Cefaclor, bromhexine, dimyristoyl phosphatidyl choline, cholesterol and the polysorbas20 of discovery specified weight proportioning can be processed the compound cefaclor medicine compound liposome, and be wherein, high as the cefaclor and the bromhexine envelop rate of active constituents of medicine; The liposome particle diameter is little and be evenly distributed; The retention time significant prolongation of active constituents of medicine in the gained solid preparation in the body circulation, bioavailability obviously improves, and curative effect obviously improves.
On the one hand, the present invention provides a kind of compound cefaclor medicine compound liposome, and it is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1: 2-1: 4.
Preferably, compound cefaclor medicine compound liposome provided by the invention is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1: 2-1: 3.
Further preferably, compound cefaclor medicine compound liposome provided by the invention is by comprising that following materials of weight proportions composition processes:
In this article, used term " compound cefaclor pharmaceutical composition " be meant cefaclor and bromhexine compositions, particularly finger spore clo and bromhexine with 250: 8 compositions of weight ratio.
As the phospholipid that is used to form liposome, it is of a great variety, and commonly used have natural phospholipid and a synthetic phospholipid.Natural phospholipid comprises Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine and soybean phospholipid acyl inositol etc.Synthetic phospholipid comprises dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, two myristoyl phosphatidylcholines, two Laurel phosphatidyl cholines, DOPG, distearyl phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two lauroyl phosphatidyl glycerols etc.
The inventor is through long-term conscientious research, through a large amount of screening tests, find to adopt general phospholipid and additives for the liposome of film material preparation under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%, stable and envelop rate is not good.The combination of the unexpected discovery dimyristoyl phosphatidyl choline of the inventor, cholesterol and these three kinds of materials of polysorbas20; The stability and the not good problem of envelop rate of liposome have been solved; Obtained beyond thought preparation effect, thereby superior in quality liposome is provided.
In common phospholipid material; The dimyristoyl phosphatidyl choline of appropriate amount can be used to form colory dimyristoyl phosphatidyl choline liposome; Method through providing among the present invention can form the liposome to excellent in stability; And the size of liposome suitably, constituent is suitable, envelop rate is high, and these compositions, and is especially non-leakage in formed liposome as the compound cefaclor pharmaceutical composition of active component.If select other phospholipid material such as soybean lecithin for use, then the poor stability of formed liposome can not be realized the object of the invention.
In compound cefaclor medicine compound liposome of the present invention, for the cefaclor of 250 weight portions, the consumption of dimyristoyl phosphatidyl choline is the 100-450 weight portion.If the consumption of dimyristoyl phosphatidyl choline is lower than 100 weight portions, have a large amount of free cephalo cefaclors and bromhexine and do not sealed, the drug loading of liposome is low, and stability also can descend; Otherwise,, then descend as the cefaclor of active constituents of medicine and the envelop rate of bromhexine if the consumption of dimyristoyl phosphatidyl choline is higher than 450 weight portions.
In compound cefaclor medicine compound liposome of the present invention, cholesterol and polysorbas20 are used to regulate the membrane stability of liposome.
Cholesterol is a kind of amphiphilic, combines with dimyristoyl phosphatidyl choline, stops it to be condensed into crystal structure.Cholesterol mixes in the dimyristoyl phosphatidyl choline duplicature, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ".When being lower than phase transition temperature, cholesterol can make film reduce ordered arrangement, increases mobile; When being higher than phase transition temperature, cholesterol can increase the ordered arrangement of film, thereby reduces the flowability of film.Cholesterol can make liposome bimolecular tunic solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
The inventor is through discovering, when cholesterol and dimyristoyl phosphatidyl choline weight ratio are 1: 2-1: in the time of 4, can form stable compound cefaclor medicine compound liposome.When cholesterol and dimyristoyl phosphatidyl choline weight ratio were higher than 1: 2, membrane stability reduced, and cefaclor and bromhexine are easy to seepage; When cholesterol and dimyristoyl phosphatidyl choline weight ratio were lower than 1: 4, the liposome membrane flowability was too high, was wrapped in intravital cefaclor of lipid and bromhexine and was easy to discharge.
In addition, discover that when the weight sum and the DSPC weight ratio of cholesterol and soyasterol is 1: 2-1: in the time of 4, formed liposome toxicity is low.
Research shows that the stability of liposome and bioavailability have close corresponding relation.Stability is high more, and bioavailability is high more.Therefore, the stability of compound cefaclor medicine compound liposome of the present invention is high, is to cause one of high factor of drug bioavailability.
In addition; The inventor discovers, in compound cefaclor medicine compound liposome of the present invention, for the cefaclor of 250 weight portions; The consumption of dimyristoyl phosphatidyl choline is the 100-450 weight portion; Cholesterol is the 20-150 weight portion, and cholesterol and dimyristoyl phosphatidyl choline weight ratio are 1: 2-1: 4 o'clock, the envelop rate of formed compound cefaclor medicine compound liposome was high.
In compound cefaclor medicine compound liposome of the present invention, use polysorbas20 further to improve the stability and the envelop rate of liposome membrane.Polysorbas20 is a kind of non-ionic surface active agent, when being used for the dimyristoyl phosphatidyl choline duplicature, can not only further improve the dissolubility of cefaclor and bromhexine, thereby improves envelop rate; And can improve the chemical energy between this duplicature, thus the chemical stability of liposome in waterborne liquid improved, and then improve the stability of compound cefaclor medicine compound liposome.
In compound cefaclor medicine compound liposome of the present invention, for the cefaclor of 250 weight portions, the consumption of polysorbas20 is the 20-150 weight portion.If the consumption of polysorbas20 is lower than 20 weight portions; Then cause improving not enough to the stability and the envelop rate of liposome owing to its consumption is low excessively; Otherwise if the consumption of polysorbas20 is higher than 150 weight portions, it is too high and cause liposome membrane to be easy to destroy and reveal active component then to be used for its consumption.
In compound cefaclor medicine compound liposome of the present invention; The collaborative adjusting facilitation to the dimyristoyl phosphatidyl choline membrane structure of cholesterol and polysorbas20 through an amount of proportioning; Can form envelop rate height, stable high compound cefaclor medicine compound liposome; Its had good sustained release effect, bioavailability is high.
On the other hand, the present invention provides the method for preparing of compound cefaclor medicine compound liposome, and this method may further comprise the steps:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, concussion is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid.
In an embodiment preferred of compound cefaclor medicine compound liposome method for preparing of the present invention; Organic solvent described in the step (a) is selected from one or more in ethanol, methanol, acetone, ether, chloroform, the normal hexane, and preferred volume ratio is 1: 3 the methanol and the mixed solvent of normal hexane.
In an embodiment preferred of compound cefaclor medicine compound liposome method for preparing of the present invention; Buffer salt solution described in the step (b) is selected from a kind of in phosphate buffered saline, carbonate buffer solution, the citrate buffer solution, and preferred pH is phosphoric acid-sodium dihydrogen phosphate buffer of 6.5.
In an embodiment preferred of compound cefaclor medicine compound liposome method for preparing of the present invention, in step (b), even matter emulsifying under 2500rpm, 0.45um filtering with microporous membrane.
In an embodiment preferred of compound cefaclor medicine compound liposome method for preparing of the present invention, in step (c), the 0.45um filtering with microporous membrane.
Through said method, can prepare the little and uniform compound cefaclor medicine compound liposome of particle size distribution of granule, its envelop rate is high, and stability is high, is difficult for leaking, and bioavailability is high.
Discover that the size of liposome is to influence the liposome principal element with the time of staying that distributes in vivo, the particle diameter of liposome is more little, and the time of staying is long more in the body.Compound cefaclor medicine compound liposome granule through the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
On the one hand, the present invention provides the compound cefaclor medicine compound liposome solid preparation again, and it is processed by compound cefaclor medicine compound liposome and other pharmaceutic adjuvants,
Wherein said compound cefaclor medicine compound liposome is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1: 2-1: 4;
Based on the cefaclor of 250 weight portions, the amount of other pharmaceutic adjuvants is 100-500 part.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation of the present invention, the compound cefaclor medicine compound liposome is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1: 2-1: 3.
In a preferred embodiment of compound cefaclor medicine compound liposome solid preparation of the present invention, the compound cefaclor medicine compound liposome is by comprising that following materials of weight proportions composition processes:
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation of the present invention, based on the cefaclor of 250 weight portions, the amount of other pharmaceutic adjuvants is the 200-375 weight portion.
In this article; The meaning of used term " other pharmaceutic adjuvants " or " pharmaceutic adjuvant " and excipient equivalent in meaning; Be meant the medicinal material except the compound cefaclor medicine compound liposome that uses in order to prepare the compound cefaclor medicine compound liposome solid preparation, comprise filler, disintegrating agent, binding agent, lubricant and combination thereof.
In this article, used term " amounts of other pharmaceutic adjuvants " is meant the weight sum of above-mentioned pharmaceutic adjuvant.
The consumption of various pharmaceutic adjuvants can be selected according to the general consumption of each adjuvant in solid preparation by those skilled in the art, and this is in those skilled in the art's limit of power.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation of the present invention, said filler is selected from one or more in starch, lactose, mannitol, sorbitol, dextrin and the sucrose, is preferably starch and mannitol.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation of the present invention; Said disintegrating agent is selected from one or more of low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, preferred polyvinylpolypyrrolidone.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation of the present invention; Said binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, sodium carboxymethyl cellulose, arabic gum, xanthan gum, methylcellulose and the ethyl cellulose, is preferably xanthan gum.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation of the present invention; Said lubricant is selected from one or more in magnesium stearate, zinc stearate, Pulvis Talci, Macrogol 4000, the stearic acid, is preferably Macrogol 4000.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation of the present invention, binder solution is 40% alcoholic solution.
Compound cefaclor medicine compound liposome solid preparation provided by the invention is an oral formulations, comprises tablet, granule and capsule.
In practice; Consider the effective dose of medicine and the convenience of medication; In the preferred embodiment of compound cefaclor medicine compound liposome solid preparation of the present invention, the specification of preparation is that per unit preparation cefaclor/bromhexine is respectively 250mg/8mg or 500mg/16mg.
On the one hand, the present invention provides the method for preparing of above-mentioned compound cefaclor medicine compound liposome solid preparation again, and this method may further comprise the steps:
(1) preparation of compound cefaclor medicine compound liposome: cefaclor, bromhexine, dimyristoyl phosphatidyl choline, cholesterol and polysorbas20 are mixed and made into lipidosome solid;
(2) preparation of compound cefaclor medicine compound liposome solid preparation: compound cefaclor medicine compound liposome and other pharmaceutic adjuvants are mixed with the compound cefaclor medicine compound liposome solid preparation, and wherein said pharmaceutic adjuvant is selected from filler, disintegrating agent, sweeting agent, lubricant and combination thereof.
In a preferred implementation of the method for preparing of compound cefaclor medicine compound liposome solid preparation, the preparation of step (1) compound cefaclor pharmaceutical composition plastid comprises following substep:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, concussion is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid.
In a preferred implementation of the method for preparing of compound cefaclor medicine compound liposome solid preparation, the preparation of step (2) compound cefaclor medicine compound liposome solid preparation comprises following substep:
(d) compound cefaclor medicine compound liposome solid and filler, disintegrating agent, sweeting agent are mixed, the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, drying;
(e) dried granule and mix lubricant is even, the granulate that sieves, tabletting, filled capsules or pack make the compound cefaclor medicine compound liposome solid preparation.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation method for preparing of the present invention; Organic solvent described in the substep (a) is selected from one or more in ethanol, methanol, acetone, ether, chloroform, the normal hexane, and preferred volume ratio is 1: 3 the methanol and the mixed solvent of normal hexane.
In an embodiment preferred of compound cefaclor medicine compound liposome solid preparation method for preparing of the present invention; Buffer salt solution described in the substep (b) is selected from a kind of in phosphate buffered saline, carbonate buffer solution, the citrate buffer solution, and preferred pH is phosphoric acid-sodium dihydrogen phosphate buffer of 6.5.
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 becomes liposome with bromhexine with the combined preparation of the specified weight of dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 through the active component cefaclor earlier, is mixed and made into solid preparation with other pharmaceutic adjuvant again.Gained solid preparation product quality is high, and particle diameter is even, and stability is high, and envelop rate is high, and medicine retention time in blood circulation is long, and is evident in efficacy; Used adjuvant cheap and simple is polluted little.
The method for preparing of compound cefaclor medicine compound liposome solid preparation provided by the invention has improved product quality, and equipment is simple, easy operating, and industrialized great production is highly advantageous to.
In this article, if not explanation especially, content or consumption are all by weight.
Embodiment
Below through concrete preferred embodiment the present invention is further specified.These embodiment only are illustrative, and should not be construed as limitation of the present invention.
As follows raw materials used:
Adopt following production technology to prepare compound cefaclor medicine compound liposome sheet:
(1) 120g dimyristoyl phosphatidyl choline, 50g cholesterol, 50g polysorbas20 being dissolved in the 400ml volume ratio is in 1: 3 the mixed solvent of methanol and normal hexane; Mix homogeneously; The mixed solvent of methanol and normal hexane is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(2) adding 500ml pH is phosphoric acid-sodium dihydrogen phosphate buffer of 6.5, and concussion is stirred and made the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying of 2500rpm, and the 0.45um filtering with microporous membrane makes the blank liposome suspension;
(3) 250g cefaclor and 8g bromhexine are dissolved in the 500ml water, the 0.45um filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid;
(4) compound cefaclor medicine compound liposome solid and 240g starch, 30g polyvinylpolypyrrolidone are mixed, cross 80 mesh sieve mix homogeneously, add 40% the alcoholic solution 100ml that contains 20% xanthan gum and prepare soft material, cross 20 mesh sieves and granulate, drying must be done granule;
(5) with dried granule and 20g Macrogol 4000 mix homogeneously, cross 20 mesh sieve granulate, tabletting makes 1000 compound cefaclor medicine compound liposome sheets.
As follows raw materials used:
Adopt following production technology to prepare compound cefaclor medicine compound liposome capsule:
(1) 300g dimyristoyl phosphatidyl choline, 80g cholesterol, 120g polysorbas20 being dissolved in the 600ml volume ratio is in 1: 3 the mixed solvent of methanol and normal hexane; Mix homogeneously; The mixed solvent of methanol and normal hexane is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(2) adding 500ml pH is phosphoric acid-sodium dihydrogen phosphate buffer of 6.5, and concussion is stirred and made the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying of 2500rpm, and the 0.45um filtering with microporous membrane makes the blank liposome suspension;
(3) 250g cefaclor and 8g bromhexine are dissolved in the 500ml water, 0.45u, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid;
(4) compound cefaclor medicine compound liposome solid and 300g starch, 50g polyvinylpolypyrrolidone are mixed, cross 80 mesh sieve mix homogeneously, add 40% the alcoholic solution 150ml that contains 10% xanthan gum and prepare soft material, cross 20 mesh sieves and granulate, drying must be done granule;
(5) with dried granule and 15g Macrogol 4000 mix homogeneously, cross 20 mesh sieve granulate, filled capsules makes 1000 compound cefaclor medicine compound liposome capsules.
As follows raw materials used:
Adopt following production technology to prepare compound cefaclor medicine compound liposome granule:
(1) 750g dimyristoyl phosphatidyl choline, 200g cholesterol, 120g polysorbas20 being dissolved in the 800ml volume ratio is in 1: 3 the mixed solvent of methanol and normal hexane; Mix homogeneously; The mixed solvent of methanol and normal hexane is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(2) adding 800ml pH is phosphoric acid-sodium dihydrogen phosphate buffer of 6.5, and concussion is stirred and made the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying of 2500rpm, and the 0.45um filtering with microporous membrane makes the blank liposome suspension;
(3) 500g cefaclor and 16g bromhexine are dissolved in the 1000ml water, the 0.45um filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid;
(4) compound cefaclor medicine compound liposome solid and 200 mannitol, 70g Aspartane, 80g polyvinylpolypyrrolidone are mixed; Cross 80 mesh sieve mix homogeneously, add 40% the alcoholic solution 250ml contain 5% xanthan gum and prepare soft material, cross 20 mesh sieves and granulate; Drying must be done granule;
(5) with dried granule and 25g Macrogol 4000 mix homogeneously, cross 20 mesh sieve granulate, pack makes 1000 bags of compound cefaclor medicine compound liposome granules.
Comparative Examples 1-3
Adopt with respectively with embodiment 1-3 in identical production technology, the material composition in will the Comparative Examples 1-3 shown in following table 1 is processed compound cefaclor medicine compound liposome sheet, capsule and granule respectively:
Raw materials used composition among the table 1 Comparative Examples 1-3
Wherein, "/" expression is not used.
The investigation of Test Example 1 liposome
The prepared lipidosome solid sample of step (3) among embodiment 1-3 and the Comparative Examples 1-3 is carried out quality investigation, mainly carry out liposome morphologic observation, particle size determination and liposome encapsulation and measure.
Wherein, liposome morphologic observation and particle size determination adopt optical microscopy and the computing of statistica5.0 statistical software to observe about 1000 to average.
Entrapment efficiency determination adopts column chromatography for separation to combine spectrophotometry; This method operating procedure is: use column chromatography the liposome in the drug solution is separated; Utilize sorbester p17 to destroy the liposome bilayer; After being discharged, medicine calculates envelop rate with HPLC method and standard control again, by formula Q
Ooze%=(W
Bag-W
Storage)/W
Bag* 100% calculates percolation ratio.
The result is shown in the following table 2.
The investigation result of table 2 liposome
Can know by table 2, gained compound cefaclor medicine compound liposome form rule among the embodiment of the invention 1-3, the size homogeneous, mean diameter is little, and envelop rate is higher, and percolation ratio is low; And gained compound cefaclor medicine compound liposome form is irregular among the Comparative Examples 1-3, and mean diameter is big, and envelop rate is low, and percolation ratio is high.
Particularly, even when adopting same production technology, compare with Comparative Examples 2,3, gained liposome outward appearance rule among the embodiment 2,3, mean diameter is little, and envelop rate is high, and seepage is low.This shows that when the composition beyond the used composition of use the present invention, the quality of gained cefaclor liposome obviously is inferior to the present invention.
Particularly, even when adopting same production technology, compare with Comparative Examples 1,3, gained liposome outward appearance rule among the embodiment 1,3, mean diameter is little, and envelop rate is high, and seepage is low.This shows that when the composition consumption was outside the composition amount ranges that the present invention limits, the quality of gained cefaclor liposome obviously was inferior to the present invention.
Test Example 2 stability and dissolution are investigated
Compound cefaclor sheet (Haizheng Medicine Stock Co., Ltd., Zhejiang Prov with compound cefaclor medicine compound liposome solid preparation sample for preparing among the embodiment 1-3 and listing; Lot number: H20050768) under the condition of 40 ℃ of high temperature, relative humidity 75% 6 months; Carry out accelerated test and investigate, the result is shown in the following table 3.
Table 3 accelerated test result
Can be known that by table 3 the compound cefaclor sheet dissolution of listing is low, content reduces obviously when quickening June, and its related substances raises; And the sample dissolution of embodiment of the invention preparation is high, quickens that content and related substance have no significant change after June.Prove absolutely the superiority of the present invention aspect raising stability and dissolution.
The test of Test Example 3 release degree is investigated
Prepared compound cefaclor medicine compound liposome solid preparation sample among embodiment 1 and the Comparative Examples 1-3 has been carried out the release degree to be investigated.This test is carried out according to first method in 2010 editions appendix XD of Chinese Pharmacopoeia drug release determination sample, and each sample result of the test of statistics has been made release profiles.
Sampling time point is in this test: 1,2,4,6,8 hours, the result saw to attach Fig. 1 and 2.
Wherein, Fig. 1 is the cefaclor release profiles:
represent embodiment 1;
representes Comparative Examples 1;
representes Comparative Examples 2,
represent Comparative Examples 3.
Can know that by Fig. 1 the cefaclor releasing effect of sample of the present invention is superior to Comparative Examples 1-3.
Fig. 2 is the bromhexine release profiles:
represent embodiment 1;
representes Comparative Examples 1,
expression Comparative Examples 2
expression Comparative Examples 3.
Can know that by Fig. 2 the bromhexine releasing effect of sample of the present invention is superior to Comparative Examples 1-3.
This shows that the stability of compound cefaclor medicine compound liposome solid preparation of the present invention and release in vitro degree are superior to Comparative Examples 1-3, have improved stability and releasing effect.
Industrial applicibility
Result by the foregoing description and experimental example can know that compound cefaclor medicine compound liposome solid preparation of the present invention has good surface appearance, and granule is little; Particle diameter is even, and envelop rate is high, and stability is high; Percolation ratio is low; The time of staying in vivo is long, and bioavailability is high, has the favorable industrial using value.
More than through the specific embodiment and embodiment the present invention is specified; But should understand; These explanations do not constitute any restriction to scope of the present invention; Under the situation that does not depart from spirit of the present invention and protection domain, can carry out multiple modification, improvement and replacement to technical scheme of the present invention and embodiment thereof, these are all because of falling in protection scope of the present invention.
Each list of references of mentioning among the application or quoting is incorporated herein by reference at this in full.
Claims (12)
1. compound cefaclor medicine compound liposome, it is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1:2-1:4,
The method preparation of this compound cefaclor medicine compound liposome through may further comprise the steps:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, vibration is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid.
2. compound cefaclor medicine compound liposome according to claim 1, it is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1:2-1:3.
3. compound cefaclor medicine compound liposome according to claim 1, it is by comprising that following materials of weight proportions composition processes:
4. the method for preparing of a compound cefaclor medicine compound liposome, said compound cefaclor medicine compound liposome is each described compound cefaclor medicine compound liposome among the claim 1-3, this method may further comprise the steps:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, vibration is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid.
5. method according to claim 4, wherein,
Organic solvent described in the step (a) is selected from one or more in ethanol, methanol, acetone, ether, chloroform, the normal hexane; And/or
Buffer salt solution described in the step (b) is selected from a kind of in phosphate buffered saline, carbonate buffer solution, the citrate buffer solution.
6. method according to claim 4, wherein,
Organic solvent described in the step (a) is the methanol of 1:3 and the mixed solvent of normal hexane; And/or
Buffer salt solution described in the step (b) is that pH is phosphoric acid-sodium dihydrogen phosphate buffer of 6.5.
7. compound cefaclor medicine compound liposome solid preparation, it is processed by compound cefaclor medicine compound liposome and other pharmaceutic adjuvants,
Wherein said compound cefaclor medicine compound liposome is by comprising that following materials of weight proportions composition processes:
Condition is: the weight ratio of cholesterol and dimyristoyl phosphatidyl choline is 1:2-1:4;
Based on the cefaclor of 250 weight portions, the amount of other pharmaceutic adjuvants is 100-500 part,
The method preparation of this compound cefaclor medicine compound liposome through may further comprise the steps:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, vibration is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid.
8. compound cefaclor medicine compound liposome solid preparation according to claim 7, wherein, based on the cefaclor of 250 weight portions, the amount of other pharmaceutic adjuvants is the 200-375 weight portion.
9. the method for preparing of a compound cefaclor medicine compound liposome solid preparation; Said compound cefaclor medicine compound liposome solid preparation is that this method may further comprise the steps according to claim 7 or 8 described compound cefaclor medicine compound liposome solid preparations:
(1) preparation of compound cefaclor medicine compound liposome: cefaclor, bromhexine, dimyristoyl phosphatidyl choline, cholesterol and polysorbas20 are mixed and made into lipidosome solid;
(2) preparation of compound cefaclor medicine compound liposome solid preparation: compound cefaclor medicine compound liposome and other pharmaceutic adjuvants are mixed with the compound cefaclor medicine compound liposome solid preparation, and wherein said pharmaceutic adjuvant is selected from binding agent, filler, disintegrating agent, sweeting agent, lubricant and combination thereof.
10. method according to claim 9, wherein the preparation of step (1) compound cefaclor pharmaceutical composition plastid comprises following substep:
(a) dimyristoyl phosphatidyl choline, cholesterol, polysorbas20 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on Rotary Evaporators, makes immobilized artificial membrane;
(b) add buffer salt solution, vibration is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) cefaclor and bromhexine is water-soluble, filtering with microporous membrane adds the blank liposome suspension in the filtrating, and 50 ℃ are incubated 30-50 minute, and spray drying makes lipidosome solid;
Organic solvent described in the substep (a) is selected from one or more in ethanol, methanol, acetone, ether, chloroform, the normal hexane;
Buffer salt solution described in the substep (b) is selected from a kind of in phosphate buffered saline, carbonate buffer solution, the citrate buffer solution.
11. method according to claim 10, wherein the organic solvent described in the substep (a) is that volume ratio is the methanol of 1:3 and the mixed solvent of normal hexane;
Buffer salt solution described in the substep (b) is that pH is phosphoric acid-sodium dihydrogen phosphate buffer of 6.5.
12. method according to claim 9, wherein the preparation of step (2) compound cefaclor medicine compound liposome solid preparation comprises following substep:
(d) compound cefaclor medicine compound liposome solid and filler, disintegrating agent, sweeting agent are mixed, the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, drying;
(e) dried granule and mix lubricant is even, the granulate that sieves, tabletting, filled capsules or pack make the compound cefaclor medicine compound liposome solid preparation.
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