CN102429867A - Dex-ibuprofen injectable suspension and preparation method thereof - Google Patents
Dex-ibuprofen injectable suspension and preparation method thereof Download PDFInfo
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- CN102429867A CN102429867A CN201110406568XA CN201110406568A CN102429867A CN 102429867 A CN102429867 A CN 102429867A CN 201110406568X A CN201110406568X A CN 201110406568XA CN 201110406568 A CN201110406568 A CN 201110406568A CN 102429867 A CN102429867 A CN 102429867A
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Abstract
The invention discloses a dex-ibuprofen injectable suspension and a preparation method thereof. The preparation consists of dex-ibuprofen, low-acyl gellan gum, carrageenan, pectin and a colloidal property reinforcing agent. The dex-ibuprofen injectable suspension prepared with the method is a thixotropic liquid, and has the characteristics of low viscosity, high suspension supporting property and permanent lamination resistance, so that the sizes of dex-ibuprofen particles can be kept stable during long-term storage.
Description
Technical field
The invention belongs to medical manufacturing field, relate to the prescription of a kind of dosage form of (S)-ibuprofen, be specifically related to a kind of (S)-ibuprofen suspension and preparation method thereof.
Background technology
(S)-ibuprofen (Dexibuprofen); Chemical name is (2s)-2-[4-(2-methylpropyl) phenyl] ropionic acid (S)-2-(+)-(4-isobutyl phenenyl) propanoic acid, is S-(+)-isomer of the NSAID ibuprofen (racemic modification) that has been widely used.
Structural formula is:
Ibuprofen is the derivant of benzenpropanoic acid, is safe and effective medicine among traditional NSAIDs, is the first ladder medicine that the medication of pain ladder is recommended.NSAID (NSAIDs) has analgesic, analgesic activity, is widely used in clinical at present.The effect of (S)-ibuprofen and ibuprofen is identical with purposes, but obviously is superior to ibuprofen in safety and pharmaco-kinetic properties (S)-ibuprofen.
(S)-ibuprofen went on the market in Austria early than 1994, was widely used in the treatment rheumatoid arthritis, the most a kind of new nonsteroidal anti-inflammatory drug.Rheumatoid arthritis (RA) is the not clear and definite as yet systemic autoimmune disease of a kind of cause of disease, can occur in muscle, tendon, ligament and joint etc. and locate.Comparatively obvious with arthropathy.After the joint involvement, bone, cartilaginous tissue are destroyed, the function of joint forfeiture, and ankylosis is tetanic, and its disability rate is high, and is very big to human harm, belongs to obstinate disease.And find the heating that (S)-ibuprofen causes the disease of catching a cold, alleviate that effect such as slight headache, pharyngalgia and the tenderness that influenza etc. cause is also obvious owing to catch a cold.(S)-ibuprofen is an ibuprofen tool medicine active single enantiomer of generation; So on using dosage, the (S)-ibuprofen that is lower than ibuprofen dosage also can produce on an equal basis even stronger pharmacological action, and do not disturb the synthetic of body fat tissue biological; Got rid of the possibility of bringing out the hyperreaction reaction; Getting into does not need in the body to transform, and the short time reaches sufficiently high blood drug level rapidly, rapid-action, effect is strong.
To cause the inflammatory epoxidase be the synthetic of medium property prostaglandin or other mediators with the arachidonic metabolism to (S)-ibuprofen through suppressing induction type, alleviates local organization hyperemia due to the prostaglandin, swelling, heating; Discharge through suppressing leukocyte activity and lysosome, reduce the sensitivity to pain of local peripheral nerve, reduce the tissue impulsion, thereby play analgesic activity algogenic substances such as Kallidin Is.The mechanism that (S)-ibuprofen is used to treat dysmenorrhea possibly be its inhibition to prostaglandin, makes that intrauterine pressure descends, uterine contraction reduces.(S)-ibuprofen also can be alleviated gout, but can not correct hyperuricemia through antiinflammatory, analgesia.In addition, this medicine also organizes prototype (physiological) epoxidase that inhibitory action is arranged to stomach, kidney etc.
(S)-ibuprofen white or off-white color crystalline powder have special smelly slightly.Dissolve point for 49-53 ℃.Very easily be dissolved in ethanol, acetone, chloroform and ether and sodium hydrate aqueous solution, water-soluble hardly.Water solublity is almost insoluble to be to influence the key factor that (S)-ibuprofen absorbs.The dosage form that present (S)-ibuprofen has gone on the market has tablet, capsule, suppository and oral administration mixed suspension.
According to the character and the market demand of (S)-ibuprofen, oral administration mixed suspension is to be superior to the comparatively ideal preparation of other oral formulations.Although tablet, capsule production efficiency are high, relatively poor because of the dispersibility of its (S)-ibuprofen, and taste is good and be difficult to be absorbed.Oral suspensions means that the microparticulate of slightly solubility solid drugs forms suspension and supplies oral liquid preparation in liquid dispersion medium.Can be in long term store particle size remain unchanged, be prone to topple over, good looking appearance, delicious taste, absorption is fast and advantages such as preparation technology's quality controllability and good stability.Compliance is good, is particularly useful for child and old people.Though the oral administration mixed suspension settling volume that has gone on the market at present ratio is near 1, but its viscosity is big, is unfavorable for drug dumping, causes drug dose inaccurate.
In view of the advantage of above (S)-ibuprofen oral administration mixed suspension and clinical needs; It is high to invent a kind of production efficiency, good dispersion, delicious taste, absorption are fast, settling volume than near 1, viscosity is little and preparation technology's quality controllability and good stability the (S)-ibuprofen oral administration mixed suspension extremely urgent.Relevant report is not still seen in (S)-ibuprofen suspension research provided by the invention at home and abroad.
Summary of the invention:
The purpose of this invention is to provide a kind of (S)-ibuprofen suspension, said preparation is made up of (S)-ibuprofen, low-acyl gellan gum, carrageenan, pectin, colloidality reinforcing agent.It is exactly a kind of thixotropic agent that low-acyl gellan gum, carrageenan, pectin, colloidality reinforcing agent are combined together, and mainly is presented as the thixotrope effect, and thixotrope has thixotropy, only uses jolting, need not heat just to make gel become colloidal sol; Need not cool off, only need leave standstill certain hour, become gel by colloidal sol again.Thixotrope is commonly used makes the stabilizing agent in the suspensoid, microgranule stably is scattered in the medium and is difficult for assembling sedimentation.
(S)-ibuprofen suspension provided by the invention has low viscosity, polymolecularity, high suspending property and never stratified advantage.Convenient for children and middle-aged and elderly people and the patient who swallows oral solid formulation difficulty use, and ensure to the accuracy of pharmaceutical quantities, improve the safety and the effectiveness of medicine, thereby promote absorption and the utilization of human body to (S)-ibuprofen.
Suspension type medicament generally means the liquid preparation of insoluble drugs Dispersion of Particles formed inhomogeneous disperse system in the liquid dispersion matchmaker.Requirement to suspensoid is: the microgranule of suspendible answers fine and even, its speed not to influence correctly measuring of dosage; Jolting can homodisperse a little; Particle size remains unchanged in long term store; Be prone to topple over; Good looking appearance, delicious taste also has certain antiseptic power; The external suspensoid should be easy to coating, is difficult for scattering, and ability rapid draing can form the protecting film that is difficult for wiping after doing.The microgranule of suspensoid generally more than 1 μ m, use wider in medical treatment by suspensoid, in oral, external, injection, eye drip, aerosol and dosage form such as long-acting, application arranged all.
Suspensoid belongs to the coarse dispersion system of thermodynamic instability.In order to increase the physical stability of suspensoid, need add the additives that can make suspensoid stable in the preparation.The thixotropy suspensoid is formed the thixotropy of utilizing thixotrope, and promptly the character of gel and colloidal sol isothermal transformation forms gel and prevents the microgranule sedimentation when leaving standstill, and becomes colloidal sol during jolting and helps pouring out, and uses the thixotropy suspending agent to help the stable of suspensoid.Have thixotropic suspensoid, viscosity becomes big automatically when resting state, forms firm RF, helps preventing the drug microparticles sedimentation.Gellan gum, carrageenan, pectin, potassium chloride that the present invention adopts, it is combined and can form thixotrope, has thixotropy, through regulating the mixed proportion of suspension, can process ideal suspension substrate.When fierce jolting, RF is destroyed, but gel state becomes flow regime, is convenient to take.
But gellan gum is claimed triumphant glue again, is a kind of macromolecule linear polysaccharide, is formed by 4 molecular elementary cell repeated polymerization of monosaccharide.Its elementary cell is by 1,2 glucose residues that 3-and 1,4-connect, and 1,1 glucuronic acid residue that 3-connects and 1,1 rhamnose residue that 4-connects is formed.Wherein glucuronic acid can be neutralized into salt-mixture by potassium, sodium, calcium, magnesium.And natural gellan gum has closed O-acyl group (glyceroyl and acetyl group).Natural or title high acyl gellan gum can form the High Elasticity and Low Hardness gel.The acetylation gellan gum generates low-acyl gellan gum after removing the O-acyl group through alkali treatment, can obtain the purification low-acyl gellan gum through filtering again, i.e. commodity gellan gum, and its relative molecular mass is about 500,000.
Carrageenan is as a kind of good coagulant, agar, gelatin and pectin etc. that instead is common.The fruit jelly elasticity made from agar is not enough, and price is higher; The shortcoming of cooking fruit jelly with gelatin be solidify with melting point low, preparation and store and all need deepfreeze; Shortcoming with pectin is that the sugar that needs to add high solubility just can solidify with the suitable pH value of adjusting.Carrageenan does not have these shortcomings, the fruit jelly high resilience of processing with carrageenan and do not have dried up property, and therefore, it becomes fruit jelly gel commonly used.
Pectin is a kind of natural polymer, has good gelatine and stable emulsifying effect, has been widely used in food, medicine, daily use chemicals and textile industry.The Fructus Citri grandis skin is rich in pectin, and its content reaches about 6%, is the desirable feedstock of producing pectin.Pectin divides three kinds of liquid pectin, jelly powder and hypo-methoxy pectin, and is wherein general with the application of jelly powder especially.
The colloidality reinforcing agent refers to the alkaline-earth metal of monovalence or bivalence, mainly plays crosslinked Denaturation.Potassium chloride among the present invention is as the colloidality reinforcing agent; Crosslinked is exactly between line style or branched chain type polymer macromolecule, to form the process that chemical bond combines; Between the molecule of line style, produce chemical bond, linear molecule is interconnected mutually, form RF and make intermolecular character; Being improved produces the process of gel or insoluble matter, and the three-dimensional polymer after crosslinked has higher intensity, elasticity and stability.
Adopt the technology of the (S)-ibuprofen suspension of above-mentioned thixotrope technology preparation:
(1) low-acyl gellan gum, carrageenan and pectin is even according to the prescription mixed, add all water of prescription water consumption 10%～20%, 90～100 ℃ are stirred 20min, make the formation settled solution; (2) potassium chloride of adding recipe quantity stirs 5min and makes dissolving; (3) (S)-ibuprofen of adding recipe quantity, after stirring, the water that adds the residue recipe quantity stirs.
Beneficial effect of the present invention: make (S)-ibuprofen form the dispersal unit of suspension, stably be scattered in the medium, low viscosity, high suspending property and be difficult for assembling sedimentation and never layering.Compare with common (S)-ibuprofen preparation, have can be in long term store particle size remain unchanged, be prone to topple over, good looking appearance, delicious taste, absorption is fast and advantages such as preparation technology's quality controllability and good stability.Compliance is good, is particularly useful for child and old people.Has good economic and social benefit.
Description of drawings
Fig. 1 is embodiment and commercially available oral administration mixed suspension
value comparison diagram
The specific embodiment
Embodiment:
Prescription:
Preparation technology: (1) adds the water of 1.5L with low-acyl gellan gum 3g, carrageenan 4g and pectin 2g mix homogeneously, and 90～100 ℃ are stirred 20min, make the formation settled solution; (2) add potassium chloride 8g, stir 5min and make dissolving; (3) (S)-ibuprofen 200g, after stirring, the water that adds the residue recipe quantity stirs.
The demonstration test of (S)-ibuprofen suspension
According to the evaluation criterion of oral administration mixed suspension, settling volume is than disperseing uniform and stable more near 1 medicine more; Viscosity is little, and single dose administration is accurate more.Viscosity/settling volume ratio is defined as
, reviews the performance of different oral administration mixed suspensions at present.Definition according to viscosity and volume settling ratio;
value is more little, and its suspension is more uniform and stable.Get the (S)-ibuprofen suspension, measure embodiment and commercially available (S)-ibuprofen oral administration mixed suspension (20100708, the only gloomy pharmaceutical Co. Ltd in Hubei) according to two appendix VI of Chinese Pharmacopoeia version in 2010 G, second method, appendix I O.Measure viscosity and settling ratio at 0d, 1d, 5d, 10d, 15d, 20d respectively.Measure the result and show that enforcement obviously is superior to commercially available sample.
The result sees table 1.
Table 1
Claims (7)
1. (S)-ibuprofen suspension and preparation method thereof, it is characterized in that: this suspension is to be the preparation that main component is processed with the (S)-ibuprofen.Said preparation is made up of (S)-ibuprofen, low-acyl gellan gum, carrageenan, pectin, colloidality reinforcing agent.
2. (S)-ibuprofen suspension according to claim 1 and preparation method thereof is characterized in that: this (S)-ibuprofen suspension is made up of following component:
3. (S)-ibuprofen suspension according to claim 2 and preparation method thereof is characterized in that: described colloidality reinforcing agent is potassium chloride or calcium lactate.
4. (S)-ibuprofen suspension according to claim 2 and preparation method thereof is characterized in that: the particle diameter of described (S)-ibuprofen is between 10～20 μ m.
5. according to claim 2,3,4 described (S)-ibuprofen suspensions and preparation method thereof, it is characterized in that: one of this (S)-ibuprofen suspension prescription is:
6. (S)-ibuprofen suspension according to claim 5 and preparation method thereof; It is characterized in that: this (S)-ibuprofen suspension method for preparing may further comprise the steps: (1) is even according to the prescription mixed with low-acyl gellan gum, carrageenan and pectin; Add all water of prescription water consumption 10%～20%; 90～100 ℃ are stirred 20min, make the formation settled solution; (2) potassium chloride of adding recipe quantity stirs 5min and makes dissolving; (3) (S)-ibuprofen of adding recipe quantity, after stirring, the water that adds the residue recipe quantity stirs.
7. (S)-ibuprofen suspension according to claim 6 and preparation method thereof is characterized in that: the viscosity of prepared (S)-ibuprofen suspension is not less than 50mpa.s.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176596A (en) * | 2016-08-03 | 2016-12-07 | 上海延安药业有限公司 | Dex-ibuprofen injectable suspension compositions and preparation method thereof |
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| US20080260837A1 (en) * | 2007-04-20 | 2008-10-23 | Qpharma, L.L.C. | Physically stable aqueous suspensions of active pharmaceuticals |
| CN101657185A (en) * | 2007-02-15 | 2010-02-24 | (株)中外制药 | thixotropic pharmaceutical compositions |
| CN101940587A (en) * | 2009-07-03 | 2011-01-12 | 山东省生物药物研究院 | Xanthan-gum-containing pharmaceutical preparation for joint intracavity injection |
| CN101991531A (en) * | 2010-11-09 | 2011-03-30 | 武汉人福药业有限责任公司 | Ibuprofen oral suspension and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101657185A (en) * | 2007-02-15 | 2010-02-24 | (株)中外制药 | thixotropic pharmaceutical compositions |
| US20080260837A1 (en) * | 2007-04-20 | 2008-10-23 | Qpharma, L.L.C. | Physically stable aqueous suspensions of active pharmaceuticals |
| CN101940587A (en) * | 2009-07-03 | 2011-01-12 | 山东省生物药物研究院 | Xanthan-gum-containing pharmaceutical preparation for joint intracavity injection |
| CN101991531A (en) * | 2010-11-09 | 2011-03-30 | 武汉人福药业有限责任公司 | Ibuprofen oral suspension and preparation method thereof |
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| CN106176596A (en) * | 2016-08-03 | 2016-12-07 | 上海延安药业有限公司 | Dex-ibuprofen injectable suspension compositions and preparation method thereof |
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Application publication date: 20120502 |