CN101627986B - Acedofenac-paracetamol pharmaceutical composite and liposome solid preparation thereof - Google Patents
Acedofenac-paracetamol pharmaceutical composite and liposome solid preparation thereof Download PDFInfo
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- CN101627986B CN101627986B CN200910017861XA CN200910017861A CN101627986B CN 101627986 B CN101627986 B CN 101627986B CN 200910017861X A CN200910017861X A CN 200910017861XA CN 200910017861 A CN200910017861 A CN 200910017861A CN 101627986 B CN101627986 B CN 101627986B
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Abstract
The invention relates to an acedofenac-paracetamol pharmaceutical composite and a liposome solid preparation thereof and a preparation method thereof; the solid preparation comprises the liposome of acedofenac-paracetamol and the excipient which is accepted in pharmacy and the liposome comprises the following components according to the parts by weight percent: 1 part of acedofenac, 5 parts of paracetamol, 5-32 parts of soybean lecithin, 2-17 parts of cholesterol, 2.5-15 parts of sodium deoxycholate and 4-24 parts of poloxamer 188.
Description
Technical field
The present invention is specifically related to a kind of solid preparation that contains aceclofenac acetaminophen medicine compound liposome and preparation method thereof, belongs to medical technical field.
Background technology
Aceclofenac was synthetic by Spain Prodesfarma the earliest, in Initial Public Offering in 1992.Appear on the market less than 10 years, country's listing is used surplus Spain, Portugal, Germany, Britain, France, Finland and Belgium etc. 20, and 1998 by income European Pharmacopoeia and British Pharmacopoeia, prove that the safety of this medicine and effectiveness have obtained extensively certainly.But clinical experiment confirms, can absorb fully rapidly behind the healthy human oral aceclofenac, and its bioavailability almost reaches 100%, and peak reaching time of blood concentration is after the medication 1.25-3 hour.It is 4-4.3 hour that average blood plasma is eliminated the half-life, and elimination factor is about 6L/h, and nearly 2/3 drug main will pass through homaluria with the hydrocarbonylation metabolite of combining form, and the prototype medicine only accounts for 1% of drug dose.
The product of domestic at present existing aceclofenac sheet, aceclofenac capsule, aceclofenac enteric coatel tablets and enteric coated capsule.A kind of compositions and preparation methods for bioavailable oral aceclofenac dosage forms is disclosed as patent documentation CN1543359A; CN1989957A discloses a kind of aceclofenac granule.Because the half-life of aceclofenac is shorter,, needed take medicine in one 2～3 times, and blood concentration fluctuation is bigger for keeping effective blood drug concentration; And sick patient such as rheumatism, rheumatoid, generally need take medicine for a long time, and then increased the risk of the toxic and side effects of medicine.The aceclofenac main adverse reaction is a gastrointestinal reaction, and as dyspepsia, stomachache, nauseating and diarrhoea, modal is dyspepsia.
Acetaminophen is pain relieving commonly used and antipyretic, and rich experience confirms that clearly it is the analgesic and analgesic of standard of light to moderate pain status.Acetaminophen is sold with the OTC (over-the-counter) over-the-counter with conventional liq, suppository, capsule, tablet and capsule tablet form in many countries.After the acetaminophen of tablet for example or capsular solid form of ingesting, the onset of drug absorption speed and pharmacologically active may be different because of the patient.For example, proved tablet form acetaminophen be absorbed in the influence that is subjected to food to a great extent and the minimum that can not always reach acetaminophen treatment concentration, these factors may relevant (people such as Stillings M. with some patient's analgesia, Current MedicalResearch and Opinion 16 (2): 115-124,2000).
The preparation that NSAID (non-steroidal anti-inflammatory drug) and acetaminophen are formed has carried out many curative effects aspect report in the document at home and abroad, proved the significant curative effect of The combined medication.The exemplary formulations of having gone on the market at present is for having introduced the tablet formulation of composition more complicated at Meng Luoying injection, the Japan Patent of the pharmaceutical composition tablet of the Parafortan sheet of India's listing, Uhrozox, domestic Guangzhou Ming Xing pharmaceutcal corporation, Ltd: acetaminophen 150rag, diclofenac sodium 15rag, caffeine 60mg, DBT (dibenzoylthiamine) 8mg.These have proved that all acetaminophen and NSAID (non-steroidal anti-inflammatory drug) are a pair of synergistic medicines that has.
Aceclofenac is better than the medicine of diclofenac as curative effect and safety, the drug combination preparation of itself and acetaminophen goes on the market in India in April, 2005, through pharmacology analysis and clinical proof aceclofenac and acetaminophen are made drug combination preparation, can play antipyretic and anti-inflammatory analgesic effect, the treatment of the pain that be applicable to osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, waist (back of the body) pain and having a toothache etc. causes and the treatment of inflammatory symptom and gynecological inflammation and ear, nose, laryngitis.Patent documentation CN101411699A discloses the tablet that contains aceclofenac and acetaminophen, conventional filleies such as adding starch are made, directly that the mixed tablet stability that gets of aceclofenac, acetaminophen and starch is relatively poor in this patent, and dissolution is relatively poor, and bioavailability is low.
From people such as late 1960s Rahman at first use liposome as pharmaceutical carrier since, continuous progress along with science and technology, liposome preparation technology is progressively perfect, and the liposome mechanism of action is further illustrated, and liposome becomes the hot technology field of current research.Verified, liposome is fit to vivo degradation, avirulence and non-immunogenicity, and the what is more important liposome can improve the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier.
The applicant imagines thus with liposome aceclofenac and acetaminophen, and expectation obtains pharmacological activity, and reduces its adverse side effect.
Summary of the invention
The defective that exists separately in view of aceclofenac and acetaminophen, and the common solid preparation of existing aceclofenac acetaminophen fails to solve above defective, the applicant develops the preparation of the liposome that contains aceclofenac acetaminophen pharmaceutical composition, not only reduced the side effect of aceclofenac, also improved the pharmacological activity of acetaminophen, alleviating rheumatic arthritis, rheumatoid arthritis, inflammation that osteoarthritis and ankylosing spondylitis cause and pain, and pain in the lumbar region, have a toothache, gynecological's pain and ear, on the inflammation and treatment of pain of nose throat, improved curative effect greatly.
The object of the present invention is to provide a kind of liposome of aceclofenac acetaminophen pharmaceutical composition.
The present invention also aims to provide a kind of solid preparation that contains the liposome of aceclofenac acetaminophen pharmaceutical composition, specifically, the combination of soybean lecithin, cholesterol, sodium deoxycholate, poloxamer 188 and active component aceclofenac and acetaminophen by certain content, adopt the thin film dispersion technology to make the liposome of aceclofenac acetaminophen, and then and certain mixed with excipients make tablet, can more effectively alleviate various pain, obtain gratifying technique effect.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of liposome of aceclofenac acetaminophen, comprise the component of weight portion meter: 1 part of aceclofenac, 5 parts of acetaminophen, soybean lecithin 5-32 part, cholesterol 2-17 part, sodium deoxycholate 2.5-15 part, poloxamer 188 4-24 parts.
As the present invention's one preferred embodiment, the liposome of above-mentioned described aceclofenac acetaminophen, comprise components by weight portions: 1 part of aceclofenac, 5 parts of acetaminophen, soybean lecithin 12-24 part, cholesterol 3-9 part, sodium deoxycholate 2-6 part, poloxamer 188 5-12 parts.
As preferably, the liposome of above-mentioned aceclofenac acetaminophen is characterized in that making by the method that comprises following steps:
(1) soybean lecithin, cholesterol, sodium deoxycholate and poloxamer 188 are dissolved in the solvent, mix homogeneously, removing desolvates makes immobilized artificial membrane;
(2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane, make the blank liposome suspension;
(3) aceclofenac and acetaminophen are dispersed in the water, add in the blank liposome suspension, make liposome turbid liquor;
(4), promptly get the liposome of aceclofenac acetaminophen with suspension lyophilization or spray drying.
Wherein, described buffer salt solution, be preferably the pharmaceutically acceptable buffer salt solution of pH value 4.2～5.6, for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer; The described buffer salt solution of preferred adding is counted 20～50 weight portions based on above weight portion.
Wherein, described solvent is an organic solvent, for example preferred in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, normal hexane one or more, and more preferably solvent is an isopropyl alcohol.
As preferably, above-mentioned aceclofenac acetaminophen liposome adds buffer salt solution and stirs and make the complete aquation of immobilized artificial membrane in the preferred steps (2), and reuse tissue mashing machine spare matter emulsifying, the one-tenth liposome turbid liquor; Perhaps, wherein in the step (3) aceclofenac and acetaminophen are dispersed in the water, add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, gets the suspension of liposome.
Further, as one of most preferred embodiment of the present invention, the liposome of above-mentioned described aceclofenac acetaminophen is to make by the method that comprises the steps:
(1) soybean lecithin, cholesterol, sodium deoxycholate and poloxamer 188 are dissolved in the isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane,, make the blank liposome suspension with the even matter emulsifying of tissue mashing machine;
(3) aceclofenac and acetaminophen are dispersed in the water, add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, gets the suspension of the liposome of aceclofenac acetaminophen;
(4), promptly get the liposome of aceclofenac acetaminophen with suspension lyophilization or spray drying.
The liposome of the aceclofenac acetaminophen of the method for the invention preparation can be mixed with tablet, soft or hard capsule by suitable mode, be used to prepare the ready to use solution that adapts with its dissolubility or the particulate powder of liquid, and pharmaceutically acceptable any regular dosage form.
Another goal of the invention of the present invention provides a kind of solid preparation that contains the liposome of aceclofenac acetaminophen, it is characterized in that comprising the liposome and the pharmaceutically acceptable excipient of the aceclofenac acetaminophen of above acquisition; Described solid preparation is preferably to comprise components by weight portions: 1 part of the liposome of aceclofenac acetaminophen, 0.01～0.5 part of filler, 0.01～0.1 part of disintegrating agent, 0.001～0.01 part of binding agent, 0.01～0.1 part of lubricant.
The above filler, disintegrating agent, binding agent, lubricant are selected from this area excipient commonly used.Those skilled in the art it is also understood that can add other pharmaceutically acceptable excipient according to actual needs makes required solid preparation.
Wherein:
Described filler is one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, calcium hydrogen phosphate preferably;
Described disintegrating agent is one or more in carboxymethylstach sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose preferably;
Described binding agent is one or more in hypromellose, starch slurry, sodium carboxymethyl cellulose preferably;
Described lubricant is one or more in Pulvis Talci, colloidality silicon dioxide, PEG6000, sodium lauryl sulphate etc. preferably.
Further, the preparation method of the solid preparation of above-mentioned aceclofenac acetaminophen comprises the steps:
(1) liposome of aceclofenac acetaminophen is pulverized, crossed 80 mesh sieves, standby;
(2) filler, disintegrating agent are pulverized, crossed 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add binding agent system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate;
(4), make the tablet of aceclofenac acetaminophen with the dried granules tabletting.
Another object of the present invention is that the liposome of aceclofenac acetaminophen is treated osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, lumbago, toothache, gynecological inflammation with the application in the medicine of gill, nose, laryngitis in preparation.
The present invention is by suitable supplementary material and proportioning thereof, and the liposome of the aceclofenac acetaminophen that makes is made the solid preparation of aceclofenac acetaminophen again with conventional excipients pharmaceutically.The solid preparation of the liposome of aceclofenac acetaminophen provided by the invention and aceclofenac acetaminophen mainly contains following advantage:
(1) aceclofenac and acetaminophen are embedded in the liposome, have solved the problem of stable difference, have improved drug effect and bioavailability, have guaranteed product quality;
(2) used soybean lecithin, cholesterol, poloxamer 188 and sodium deoxycholate degradation in vivo, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) production technology is simple, and cost is low, can industrial-scale production;
(4) tablet of aceclofenac acetaminophen is rapid-action, and it is obvious to alleviate various pain effects.
The solid preparation of aceclofenac acetaminophen provided by the invention carries out stability test and investigates, and accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change.
The solid preparation of aceclofenac acetaminophen provided by the invention carries out acute toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof.
The preparation technology of liposome is ripe already, prior art also discloses multiple preparation technology, for example CN101391098A discloses a kind of melittin Liposomal formulation, it is characterized in that being made up of 1 part of melittin, soybean phospholipid 5-40 part, cholesterol 1.3-10 part, poloxamer 10-140 part.CN1813678A discloses a kind of Hepatitis B virus vaccine liposome, and wherein phospholipid can be selected from lecithin, cephalin, soybean phospholipid, hydrogenated phospholipid; Ionic surfactant is selected from sodium cholate, sodium deoxycholate, or nonionic surfactant is selected from spans, Tweens, poloxamer.Application 200710175540.3 discloses a kind of preparation method of liposome, it is characterized in that this method is: get injection soybean phospholipid 300-500 weight portion, cholesterol 80-150 weight portion and be dissolved in the 10-40 parts by volume ether, sinomenine hydrochloride 30-70 weight portion is dissolved in the 5-20 parts by volume pH7.1-7.5 phosphate buffer that contains 30-70 weight portion sodium cholate as water as organic facies; Under stirring water is dropwise added in the organic facies, wait to dropwise and continue to stir 10-30 minute, obtain water/oil type emulsion; Rotary evaporation eliminates ether; Continue under the room temperature to stir and promptly got drug-loaded liposome in 20-40 minute.The embodiment 1 of application 200810155948.9 discloses the liposome of paclitaxel, comprises: paclitaxel 1g, soybean phospholipid 30g, Tween 80 1g, sodium deoxycholate 1g, cholesterol 3g, mannitol 60g, water 600mL.
Those skilled in the art should fully understand, though the preparation technology of liposome generally obtains, but each composition classification of formation liposome and the selection of content and non-obvious thereof, the applicant need pay the liposome with excellent encapsulation rate that performing creative labour just can obtain the certain ingredients proportioning.Following examples will prove creative place of the present invention one by one.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
Embodiment 1
The preparation of the liposome of aceclofenac acetaminophen
Prescription:
Aceclofenac 100g
Acetaminophen 500g
Soybean lecithin 1200g
Cholesterol 300g
Sodium deoxycholate 200g
Poloxamer 188 500g
Preparation technology
(1) 1200g soybean lecithin, 300g cholesterol, 200g sodium deoxycholate and 500g poloxamer 188 are dissolved in the 8000ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) phosphoric acid-sodium dihydrogen phosphate buffer 2000ml of adding pH=4.2 stirs and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying 20min, and rotating speed 12000r/min makes the blank liposome suspension; (aceclofenac 100g is 1 part, and buffer solution 2000ml is 2000g, 2000g/100g=20 part)
(3) 100g aceclofenac and 500g acetaminophen are dispersed among the water 5000ml, add in the blank liposome suspension, be incubated 65 ℃, reuse tissue mashing machine spares matter emulsifying 10min, gets the liposome turbid liquor of aceclofenac acetaminophen;
(4), promptly get the liposome of aceclofenac acetaminophen with the suspension lyophilization.
Comparative Examples 1
The preparation of the liposome of aceclofenac acetaminophen
Prescription:
Aceclofenac 100g
Acetaminophen 500g
Soybean lecithin 1200g
Cholesterol 300g
Poloxamer 188 500g
Preparation technology chooses non-preferred ingredient combination of the present invention with embodiment 1, makes the liposome of aceclofenac acetaminophen.
Comparative Examples 2
The preparation of the liposome of aceclofenac acetaminophen
Prescription:
Aceclofenac 100g
Acetaminophen 500g
Soybean lecithin 1200g
Cholesterol 300g
Sodium deoxycholate 200g
Preparation technology chooses non-preferred ingredient combination of the present invention with embodiment 1, makes the liposome of aceclofenac acetaminophen.
Embodiment 2
The preparation of the liposome of aceclofenac acetaminophen
Prescription:
Aceclofenac 100g
Acetaminophen 500g
Soybean lecithin 2400g
Cholesterol 900g
Sodium deoxycholate 600g
Poloxamer 188 1200g
Preparation technology
(1) 2400g soybean lecithin, 900g cholesterol, 600g sodium deoxycholate and 1200g poloxamer 188 are dissolved in the 18000ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) citric acid-sodium citrate buffer solution 5000ml of adding pH=5.6 stirs and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying 15min, and rotating speed 15000r/min makes the blank liposome suspension;
(3) 100g aceclofenac and 500g acetaminophen are dispersed among the water 5000ml, add in the blank liposome suspension, be incubated 55 ℃, reuse tissue mashing machine spares matter emulsifying 20min, gets the liposome turbid liquor of aceclofenac acetaminophen;
(4), promptly get the liposome of aceclofenac acetaminophen with the suspension spray drying.
Comparative Examples 3
Distinct methods prepares the liposome of aceclofenac acetaminophen
Prescription:
Aceclofenac 100g
Acetaminophen 500g
Soybean lecithin 2400g
Cholesterol 900g
Sodium deoxycholate 600g
Poloxamer 188 1200g
Preparation technology
(1) 100g aceclofenac, 500g acetaminophen, 2400g soybean lecithin, 900g cholesterol, 600g sodium deoxycholate and 1200g poloxamer 188 are dissolved in the 23000ml isopropyl alcohol, mix homogeneously, add pH=5.6 citric acid-sodium citrate buffer 500ml, the even at a high speed matter emulsifying 15min of tissue mashing machine, rotating speed 15000r/min, isopropyl alcohol is removed in decompression, gets the liposome turbid liquor of aceclofenac acetaminophen;
(2), promptly get the liposome of aceclofenac acetaminophen with the suspension spray drying.
Embodiment 3
The preparation of the tablet of aceclofenac acetaminophen
Select the liposome 600g (containing aceclofenac 100g, acetparaminosalol (from embodiment 1) phenol 500g) of aceclofenac acetaminophen for use
Microcrystalline Cellulose 76g
Lactose 50g
Polyvinylpolypyrrolidone 40g
Hypromellose 3g
Colloidality silica 1 5g
Pulvis Talci 20g
Preparation technology
(1) liposome that contains 600g aceclofenac acetaminophen of embodiment 1 preparation is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 76g microcrystalline Cellulose, 50g lactose, 40g polyvinylpolypyrrolidone, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 2% hypromellose, 50% alcoholic solution 150ml system soft material, to cross 20 mesh sieves and granulate, 18 mesh sieve granulate are crossed in 60 ℃ of oven dry;
(4), make the tablet of aceclofenac acetaminophen with the dried granules tabletting.
Embodiment 4
The preparation of the tablet of aceclofenac acetaminophen
Select the liposome 600g (containing aceclofenac 100g, acetparaminosalol (from embodiment 2) phenol 500g) of aceclofenac acetaminophen for use
Pregelatinized Starch 54g
Lactose 68g
Carboxymethylstach sodium 52g
Hypromellose 3g
Pulvis Talci 20g
Preparation technology
(1) liposome that contains 600g aceclofenac acetaminophen of embodiment 2 preparations is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 54g pregelatinized Starch, 68g lactose, 52g carboxymethylstach sodium, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 2% hypromellose, 50% alcoholic solution 150ml system soft material, to cross 20 mesh sieves and granulate, 55 ℃ of oven dry add 20g Pulvis Talci mix homogeneously, 18 mesh sieve granulate;
(4), make the tablet of aceclofenac acetaminophen with the dried granules tabletting.
Comparative Examples 4
The preparation of the tablet of aceclofenac acetaminophen
Select the liposome 600g (containing aceclofenac 100g, acetparaminosalol (from Comparative Examples 1) phenol 500g) of aceclofenac acetaminophen for use
Microcrystalline Cellulose 76g
Lactose 50g
Polyvinylpolypyrrolidone 40g
Hypromellose 3g
Colloidality silica 1 5g
Pulvis Talci 20g
Preparation technology is with embodiment 3, and the liposome that adopts Comparative Examples 1 preparation makes the tablet of aceclofenac acetaminophen as active component.
Comparative Examples 5
The preparation of the tablet of aceclofenac acetaminophen
Select the liposome 600g (containing aceclofenac 100g, acetparaminosalol (Comparative Examples 3) phenol 500g) of aceclofenac acetaminophen for use
Pregelatinized Starch 54g
Lactose 68g
Carboxymethylstach sodium 52g
Hypromellose 3g
Pulvis Talci 20g
Preparation technology is with embodiment 4, and the liposome that adopts Comparative Examples 3 preparations makes the tablet of aceclofenac acetaminophen as active component.
Comparative Examples 6
The tablet that the specific embodiment of employing prior art CN101411699A makes.
Test example 1
The mensuration of envelop rate
Get the Liposomal formulation of embodiment 1-2 and Comparative Examples 1-3 preparation, the total content that high performance liquid chromatography detects aceclofenac and acetaminophen is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak more than the swelling 12h with the pH6.8 phosphate buffer, pack in the chromatographic column (200 * 10mm) into, with above-mentioned phosphate buffer flushing balance, getting the aceclofenac acetaminophen liposome that embodiment 1-2 and Comparative Examples 1-3 obtain respectively is dissolved in water, make the solution that every 1ml contains the about 20mg of aceclofenac, get solution 1.8ml respectively and add the chromatographic column top, with phosphate buffer 50ml eluting, flow velocity 1.4ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=6: 1), mixing, the content M of high performance liquid chromatography detection aceclofenac and acetaminophen
1
Envelop rate %=M
1/ M * 100%.
Table 1 entrapment efficiency determination result
| Embodiment | Embodiment 1 | Comparative Examples 1 | Comparative Examples 2 | Embodiment 2 | Comparative Examples 3 |
| Envelop rate | 90.4％ | 57.7％ | 55.4％ | 88.6％ | 54.3％ |
By above result as can be known, the liposome encapsulation that the present invention makes is very high, meets the actual production requirement substantially; The liposome encapsulation that the Comparative Examples of the Comparative Examples of proportioning and Different Preparation makes and the scope of the invention is write out a prescription outward is very low, has compared tangible gap with embodiment, is not suitable for production requirement.
Test example 2
The detection of particle diameter
Get the liposome of embodiment 1-2 and Comparative Examples 1-3 preparation, adopt micro-image analyzer to measure the particle size distribution of liposome, result such as table 2:
Table 2 particle diameter testing result
By above result as can be known, the liposome that embodiment 1-2 makes shows spherical, ellipticity, and particle diameter is even, and scope is 100-200nm; The liposome shape that Comparative Examples 1-3 makes is indefinite, not of uniform size, and particle diameter is inhomogeneous, and scope is 600-900nm.
Test example 3
Study on the stability
With the sample of the embodiment 3-4 among the present invention and Comparative Examples 4-6 preparation accelerated test 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, detect the variation of every leading indicator, the results are shown in Table 3.
Table 3 accelerated test result
By above experimental result as seen, the sample dissolution height of embodiment of the invention 3-4 preparation, good stability quickened after 6 months, and every detection index does not almost have obvious variation; And the sample dissolution of Comparative Examples 4-6 preparation is low, poor stability, and it is bigger to quicken after 6 months every change detected.Proved absolutely superiority of the present invention.
Describe the preferred embodiments of the invention in this article, be included as enforcement known for inventor best mode of the present invention.The variation of those embodiment preferred can become apparent after reading above-mentioned explanation for the ordinary skill in the art.The inventor expects that the technical staff takes the circumstances into consideration to use this class and changes, and the inventor is intended to the present invention and can implements according to being different from specifically described mode herein.Therefore, the institute that the present invention includes the theme of describing in the claims herein changes and coordinate, and this is that applicable law allows.Yet any combination of the various possible variations of above-mentioned key element all be the present invention includes, unless have in addition herein explanation or with the obvious contradiction of context.
Claims (6)
1. the liposome of an aceclofenac acetaminophen, make by following method:
(1) 1200g soybean lecithin, 300g cholesterol, 200g sodium deoxycholate and 500g poloxamer 188 are dissolved in the 8000ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) phosphoric acid-sodium dihydrogen phosphate buffer 2000ml of adding pH=4.2 stirs and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying 20min, and rotating speed 12000r/min makes the blank liposome suspension;
(3) 100g aceclofenac and 500g acetaminophen are dispersed among the water 5000ml, add in the blank liposome suspension, be incubated 65 ℃, reuse tissue mashing machine spares matter emulsifying 10min, gets the liposome turbid liquor of aceclofenac acetaminophen;
(4) with the suspension lyophilization, promptly.
2. the liposome of an aceclofenac acetaminophen, make by following method:
(1) 2400g soybean lecithin, 900g cholesterol, 600g sodium deoxycholate and 1200g poloxamer 188 are dissolved in the 18000ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) citric acid-sodium citrate buffer solution 5000ml of adding pH=5.6 stirs and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying 15min, and rotating speed 15000r/min makes the blank liposome suspension;
(3) 100g aceclofenac and 500g acetaminophen are dispersed among the water 5000ml, add in the blank liposome suspension, be incubated 55 ℃, reuse tissue mashing machine spares matter emulsifying 20min, gets the liposome turbid liquor of aceclofenac acetaminophen;
(4) with the suspension spray drying, promptly.
3. the solid preparation of an aceclofenac acetaminophen is characterized in that described solid preparation is the following component that comprises by weight: 0.01～0.1 part of 1 part of the liposome of claim 1 or 2 described aceclofenac acetaminophen, 0.01～0.5 part of filler, 0.01～0.1 part of disintegrating agent, 0.001～0.01 part of binding agent and lubricant.
4. the solid preparation of aceclofenac acetaminophen according to claim 3, wherein: described filler is selected from one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate;
Described disintegrating agent is selected from one or more in carboxymethylstach sodium, polyvinylpolypyrrolidone, the cross-linking sodium carboxymethyl cellulose; Described binding agent is selected from one or more in hypromellose, starch slurry, the sodium carboxymethyl cellulose; Described lubricant is selected from one or more in Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate.
5. the method for the solid preparation of an aceclofenac acetaminophen for preparing claim 3 or 4 is characterized in that this solid preparation is a tablet, comprises the steps: that (1) pulverize the liposome of aceclofenac acetaminophen, crosses 80 mesh sieves, and is standby; (2) filler, disintegrating agent are pulverized, crossed 80 mesh sieves, mix, standby; (3) with above-mentioned supplementary material mix homogeneously, add binding agent system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate; (4) with the dried granules tabletting.
6. the application of the liposome of claim 1 or 2 described aceclofenac acetaminophen in the medicine of preparation treatment osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, lumbago, toothache.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910017861XA CN101627986B (en) | 2009-08-14 | 2009-08-14 | Acedofenac-paracetamol pharmaceutical composite and liposome solid preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910017861XA CN101627986B (en) | 2009-08-14 | 2009-08-14 | Acedofenac-paracetamol pharmaceutical composite and liposome solid preparation thereof |
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| CN106619676A (en) * | 2016-11-17 | 2017-05-10 | 郑州郑先医药科技有限公司 | Painkiller for relieving toothache |
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