CN102389401B

CN102389401B - Dexibuprofen particles and preparation method thereof

Info

Publication number: CN102389401B
Application number: CN201110373149.0A
Authority: CN
Inventors: 陆荣政; 徐卓业; 文意芬
Original assignee: Individual
Current assignee: Nanjing Zenkom Pharmaceutical Co ltd
Priority date: 2011-11-22
Filing date: 2011-11-22
Publication date: 2013-05-22
Anticipated expiration: 2031-11-22
Also published as: CN102389401A

Abstract

The invention discloses dexibuprofen particles and a preparation method thereof. According to the invention, appropriate auxiliary materials are combined with dexibuprofen, such that dexibuprofen is subject to self-emulsification in gastrointestinal tracts, and is maintained an emulsion. Compared with common dexibuprofen preparations, the dexibuprofen particles provided by the invention has advantages of good dissolution rate, high absorption speed, good controllability of preparation technological quality, good stability, and the like. The invention provides a dexibuprofen preparation with higher security, better curative effect, simpler preparation technology and good stability.

Description

A kind of (s)-ibuprofen granules and preparation method thereof

Technical field

The invention belongs to medical manufacturing field, relate to a kind of novel form of (S)-ibuprofen, be specifically related to a kind of (s)-ibuprofen granules and preparation method thereof.

Background technology

(S)-ibuprofen is the S-(+)-isomer of the NSAID (non-steroidal anti-inflammatory drug) ibuprofen (racemic modification) that has been widely used, went on the market in Austria in 1994, be used for the treatment of rheumatoid arthritis, the racemic compound that is widely used clinically, its antiinflammatory action suppresses the synthetic of prostaglandin by the S-isomer and produces.Now illustrated the R-isomer and changed into its S-isomer through a kind of CoA thioesterase intermediate in vivo, the generation of R-ibuprofen coenzyme A is emulative has suppressed many reactions that depend on coenzyme A, thereby hepatocyte intermediate supersession and mitochondrial function are produced interference.Therefore, the advantage of the S-ibuprofen of application of pure is mainly can reduce dosage and reduce side effect.

1. pharmacology

The beginning of the nineties, the discovery human body such as Needleman had 2 kinds of different Cycloxygenases (COX) isomer, i.e. COX-1 and COX-2.COX-1 is normal, structural composition in body, and it regulates physiological prostaglandin in histoorgan.COX-2 is present in inflammation part, as synovial cell, endotheliocyte and macrophage.Under the effect of extraneous stimulating factor (as IL-1), COX-2 impels synthesizing of inflammatory mediator prostaglandin and brings out inflammatory reaction.

(S)-ibuprofen has the effect that suppresses COX under clinical effective dose, and left-handed ibuprofen does not have this effect.Therefore these two kinds of space corresponding compounds are fully different on the pharmacology, can regard two kinds of different medicines as.People in animal experiment, have confirmed that with the COX-1 and the COX-2 isozyme that separate the present (S)-ibuprofen of understanding is than the high efficiency of left-handed ibuprofen.Left-handed ibuprofen does not almost have activity to COX-2.In Mice Body, the absorption of DL ibuprofen and (S)-ibuprofen does not have difference.But pure (S)-ibuprofen and DL ibuprofen human bioavailability are relatively, and (S)-ibuprofen is with respect to DL ibuprofen bioavailability average out to 0.66.When the DL ibuprofen entered human body, the left-handed ibuprofen of 50%-60% became (S)-ibuprofen by " metabolic counter-rotating ".Therefore have the people to propose, obtain the identical clinical efficacy of a certain dosage DL ibuprofen, the dosage of (S)-ibuprofen should be 75% of DL ibuprofen.But in calendar year 2001, Evans points out, above-mentioned " counter-rotating " ignored in this reasoning according to pharmacokinetics is not that such fact occurs at once.And the degree that between individuality, counter-rotating occurs has transmutability, and the kinetics of counter-rotating has difference according to the dosage saturation.Studies show that recently only needs the (S)-ibuprofen of DL ibuprofen one half-value dose just can obtain the clinical efficacy identical with the former.The 200mg of double-deck sugar-coat and the (S)-ibuprofen sheet of 400mg can absorb rapidly (Tmax2.1～2.2 hour) after oral and reach peak concentration 12.4mg/ml (200mg), 12.0mg/ml (400mg) in human body.

The metabolic characteristic of (S)-ibuprofen and left-handed ibuprofen is also different, left-handed ibuprofen is relevant with the lipid metabolism path, and be incorporated into together on triglyceride with the endogenous fatty acid, and (S)-ibuprofen and these special metabolic responses are irrelevant, therefore, (S)-ibuprofen is removed more thoroughly than DL ibuprofen in body.

2. analgesic activity

The people such as Dionne had once estimated the effect of non-peptide level in acute pain that (S)-ibuprofen causes oral surgery and blood plasma.Discovery is in initial 60 minutes, and the analgesic effect of 200mg and 400mg (S)-ibuprofen obviously is better than DL ibuprofen and the placebo of 400mg.The analgesic effect of the 2nd and the 3rd hour 400mg (S)-ibuprofen is still stronger.The time that in all patient's blood plasma, non-peptide descends occurs conforming to analgesic effect.Compare with the DL ibuprofen, give the (S)-ibuprofen of DL ibuprofen one half-value dose, just can obtain even better clinical efficacy identical with the former, can produce analgesic effect faster, higher analgesia peak value, similar effect time limit and lower rate of side effects.Its mechanism of action is except by suppressing prostaglandin synthetic, and that can suppress pituitary adrenal axis simultaneously causes the pain activity.

3. antiinflammatory, anti rheumatism action

8 groups of clinical researches that comprised 1463 routine patients according to the GCP design show, are 0.5: 1 o'clock at dose ratio, and (S)-ibuprofen is equivalent with the DL ibuprofen at least.Be equivalent to two chloric acid phenol equivalences of (S)-ibuprofen and the maximum dose level on the 100% of day maximum dose level 75%.Do not find that diet produces obviously impact to bioavailability and dose-effect relationship.(S)-ibuprofen to rheumatoid arthritis, ankylosing spondylitis, coxitis gonarthritis, lumbar vertebra syndrome, ankle joint distortion effectively.The new analysis-by-synthesis standard of the use such as Rahlfs has re-started assessment to the research of relevant (S)-ibuprofen curative effect.In 6 researchs for the treatment of rheumatoid arthritis, ankylosing spondylitis, coxitis, gonarthritis, lumbar vertebral syndrome, ankle joint distortion, it is effective that result is similarly.In effectiveness study to 178 routine coxitis patients, improve and find by estimating the WOM-ACOA index, (S)-ibuprofen 400mg every day 3 times and DL ibuprofen 800mg every day, the curative effect of 3 times equated.(S)-ibuprofen has obvious dose-effect relationship, and has critical advantage (P=0.055).Show in double blinding contrast experiment to 110 routine gonarthritis patients, every day, the curative effect of 3 300mg (S)-ibuprofens was better than the two chloric acid phenol of 3 50mg every day.

4. safety

Compare with other NSAID, (S)-ibuprofen has good toleration: DL ibuprofen rate of side effects is 30%, and two chloric acid phenol are up to 90%r.Long-term safety experiment shows, the rate of side effects of (S)-ibuprofen is only 15.2%, the wherein suitable reaction 11.7% of digestion, reaction of central nervous system 1.3%, dermoreaction 1.3%, other 0.9%, toleration is good.After open application, the investigation of larger samples amount shows that rate of side effects is 2.3%～2.7%.It combines the high efficiency of two chloric acid phenol and the safety of ibuprofen, and using value is not less than the C0X-2 inhibitor of a new generation.

5, untoward reaction

Symptom of digestive tract comprises dyspepsia, stomach burn feeling, stomachache, feels sick, vomits, and comes across 16% long-term taking person, and the drug withdrawal above-mentioned symptom disappears, and not drug withdrawal person major part also can tolerate.Gastric ulcer and digestive tract hemorrhage appear in minority (≤1%), also have because of perforated ulcer person; Neurological symptom as the headache, drowsiness, dizzy, tinnitus is rare, appears at 1%～3% patient; Renal insufficiency is rarely found, and mostly occurring is having potentiality nephropathy change person; But edema of lower limbs can appear in minority user; Other rare symptom has erythra, bronchial asthma attack, the rising of liver enzyme, leukopenia etc.; As the situations such as gastrointestinal hemorrhage, liver, renal function injury, visual disorder, hemogram abnormity and anaphylaxis occurring, namely answer drug withdrawal during medication.

According to the research of different authors, rat can be used as the Umklapp process research that suitable animal model is studied racemic ibuprofen and enantiomer thereof, because the fundamental mechanism of metabolism chiral inversion is consistent in human body and rat.Yet, be to exist difference aspect counter-rotating speed.In tissue and rat, small intestine can be used as in the appropraite condition lower body and external metabolism counter-rotating and non-metabolism counter-rotating research.Counter-rotating efficient and enantiomer preference to key enzyme (acetyl-CoA-synthetase) seem to have the kind dependency.S (+) ibuprofen opposite with the mankind, that rat may reverse a small amount of.Yet, in this research, give R (-) determination of ibuprofen that S (+) the ibuprofen counter-rotating after pure S (+) ibuprofen obtains and can not be ignored, approached quantitative limit.And R (-) ibuprofen that gives after recrystallization almost completely reverses, and has further proved the height counter-rotating ability of rat.

Some researcheres are found the clean counter-rotating amount of human body and rat between 50-60%, due to counter-rotating-independent (elimination) factor (glucal anhydride).Yet tissue is slower than liver tissues of rats homogenate at external epimerism to R (-) ibuprofen.In this research, simple reaching without the enantiomer of metabolism pointed out in the plasma concentration of rat, and rat can almost all be changed R (-) ibuprofen of administered dose into S (+) ibuprofen in 22-25min.

When front system inversion occured, each racemization kind of crystalline amount was consistent, also similar with the racemization kind of crystalline with R (-) ibuprofen of total counter-rotating, is perhaps due to the similar time of staying being arranged in intestinal.

In the rat body, after a large amount of liver sausage circulations, ibuprofen enantiomer and counter-rotating thereof and non-counter-rotating metabolite have precedence over bile excretion.This can explain the plasma concentration Cmax of ibuprofen enantiomer of non-fasting rat and the diffusion of tmax, also can explain and deliver the different of document.Sattari and Jamali use comparative test, give rat racemic ibuprofen 20mg/kg, and enantiomer has higher AUC and blood plasma tmax as a result.

The experimental design expectation obtains the blood specimen collection condition of Study on Subchronic subsequently.In order to make rat serum in the high risk minimization of loss of anesthesia, measured 4 rats separately blood drug level rather than record plasma concentration curve separately.To limit rat in order watching for animals as far as possible and to use number.The data analysis evaluation methodology will be adjusted according to concrete detection case.Can reach a conclusion according to this result of study: the ibuprofen kind of doctor's character changes crystalline nature can not cause the difference of oral formulations behavior as a result.Contain the clinical trial of modifying S (+) Genpril and show better efficacy and saferry.

6, drug interaction

Increase gastrointestinal side effect when (1) using simultaneously with other nonsteroidal antiinflammatory drugs, and the danger of the ulcer of causing is arranged.Long-term and acetaminophen can increase toxic and side effects to kidney with the used time;

(2) with aspirin and same used time of other Salicylates, drug effect does not strengthen, and gastrointestinal side effect and class origin tendency incidence rate increase;

(3) focusing on depressant with the anticoagulation such as heparin, dicoumarol and platelet has with the used time and increases hemorrhage danger;

(4) with the same used time of FRUSEMIDE, the latter's row's sodium and hypotensive effect weaken;

(5) with verapamil, same used time of nifedipine, the blood drug level of this product increases;

(6) this product can improve the blood concentration of digoxin, and the thing used time must be noted that to adjust the dosage of digoxin;

(7) this product can strengthen the antidiabetic drug effect of (comprising oral antidiabetic drug);

(8) this product and resisting hypertension can affect the latter's hypotensive effect with the used time;

(9) probenecid can reduce the excretion of this product, increases its blood drug level, thereby increases toxicity, therefore with the dosage of appropriate to the occasion minimizing this product;

(10) this product can reduce the excretion of methotrexate, increases its blood concentration, even can reach poisoning level, thus this product not should with in or high-dose methotrexate with using.

7, untoward reaction

(S)-ibuprofen is compared with other NSAID, and good toleration is arranged: the ibuprofen rate of side effects is 30%, and two chloric acid phenol are up to 90%.The rate of side effects of (S)-ibuprofen is only 15.2%, wherein digestive tract reaction 11.7%, reaction of central nervous system 1.3%, dermoreaction 1.3%, other 0.9%, toleration is good.It combines the high efficiency of two chloric acid phenol and the safety of ibuprofen, and using value is not less than the COX2 inhibitor of a new generation.Main adverse reaction is as follows:

(1) symptom of digestive tract comprises dyspepsia, stomach burn feeling, stomachache, feels sick, vomits, comes across 16% long-term taking person, and the drug withdrawal above-mentioned symptom disappears, and not drug withdrawal person major part also can tolerate.Gastric ulcer and digestive tract hemorrhage appear in minority (≤1%), also have because of the gastric ulcer borer;

(2) neurological symptom as headache, drowsiness, tinnitus is rare, 1%～3% patient occurs;

(3) renal insufficiency is rarely found, and mostly occurring is having potentiality nephropathy change person; But edema of lower limbs appears in minority user;

(4) other rare symptoms have erythra, bronchial asthma attack, the rising of liver enzyme, leukopenia etc.;

(5) during medication as the situations such as gastrointestinal class origin, liver, renal function injury, visual disorder, hemogram abnormity and anaphylaxis, drug withdrawal immediately occur.

8, points for attention

(1) be used for the late pregnancy women pregnancy period is extended, cause difficult labour and prolonged labor.Pregnant and lactant women should not use;

(2) platelet aggregation is had inhibitory action, can make hemorrhage time lengthening, but drug withdrawal 24h can disappear;

(3) blood urea nitrogen and serum flesh liver are raise, the CCr rate descends;

(4) this product is the symptomatic treatment medicine, is used for analgesic continuous application and must not surpasses 3 days, is used for pain relieving and must not surpasses 5 days, and symptom is not alleviated asks Ref Dr or pharmacist;

(5) person should be cautious use of to have the following situations

1. original bronchial asthma person can increase the weight of after medication;

2. cardiac insufficiency, hypertension, can cause water retention, edema after medication;

3. hemophilia or other hemorrhages (comprising blood coagulation disorders and platelet function abnormality), after medication, the bleeding time extends, and bleeding tendency increases the weight of;

4. digestive tract ulcer medical history person is arranged, be prone to gastrointestinal side effect when using this product, comprise producing new ulcer;

5. after renal insufficiency person medication, the kidney untoward reaction increases, and even causes renal failure;

6. should make regular check on hemogram and liver, renal function during long-term prescription.

(S)-ibuprofen is the d-isomer of ibuprofen, and this product is white or off-white color crystalline powder, slightly has special smelly, almost tasteless.English Dexibuprofen by name, general (2s)-2-[4-(2-methylpropyl) phenyl by name] ropionic acid.Molten point is 49-53 ℃.Very easily be dissolved in ethanol, acetone, chloroform and ether and sodium hydrate aqueous solution, water-soluble hardly.

Structural formula is:

Storage requirement: sealing is shady and cool preserves.

Although (S)-ibuprofen has solved the shortcomings such as the width effect of ibuprofen aspect pharmacodynamics on probation and pharmacokinetics is large, dosage is large.But its dissolubility in water is substantially constant, is difficult for making the liquid dosage form that can dissolve, and now dosage form is still the ordinary preparations such as tablet, capsule, and is the same with other NSAID (non-steroidal anti-inflammatory drug) (NSAIDS), and absorption difference, bioavailability is low, onset is relatively slow.For the problems referred to above, (s)-ibuprofen granules research provided by the invention still has no relevant report at home and abroad.

Summary of the invention:

The purpose of this invention is to provide a kind of (s)-ibuprofen granules, adopted the self-emulsifying drug delivery system, solve the existing not good characteristic of (S)-ibuprofen preparation dissolving out capability, thereby promote human body to absorption and the utilization of (S)-ibuprofen.

Self-emulsifying drug delivery system (SEDDS): the solid or the liquid preparation that are formed by oil phase, surfactant (SA), cosurfactant (CoSA), its basic feature is can be in the situation that in gastrointestinal tract or ambient temperature suitable (being often referred to 37 ℃) and gentle agitation, it is the Emulsion of 5 microns left and right that spontaneous emulsification becomes particle diameter.When containing hydrophilic SA (hydrophile-lipophile balance value＞12) higher (＞400%) or using CoSA simultaneously, can make meticulous Emulsion (particle diameter＜100 nanometers) under mild agitation, this meticulous Emulsion is called as self-micro-emulsification medicine-releasing system MEDDS.The SEDDS preparation can improve the dissolubility of insoluble drug and fat-soluble medicine, promotes infiltration rate and the degree of medicine, improves the bioavailability of medicine, can avoid the hydrolysis of water unstable medicine and medicine to the pessimal stimulation of gastrointestinal simultaneously.SEDDS also has the advantages such as taking convenience, simple, the suitable large-scale production of preparation.

The general emulsifying agent that adopts high HLB of self-emulsifying drug delivery system.The self-emulsifying drug delivery system will be in gastrointestinal tract self emulsifying and keep the Emulsion state, needing in prescription has emulsifying agent, but a large amount of emulsifying agents may stimulating gastrointestinal the road, so should take into full account the safety of emulsifying agent.The strongly hydrophilic of high HLB emulsifying agent is to form immediately oil-in-water emulsion droplet and self emulsifying liquid to spread necessaryly in water environment, and it can make the self emulsifying process faster.Emulsifying agent is amphiphatic, and itself also can dissolve relatively a large amount of hydrophobic drugs, can prevent that medicine from depositing in gastrointestinal tract and the dissolved state of prolong drug molecule, and this is extremely important to effective absorption.Emulsifying agent comprises lecithin, horse brother, peregal, milky white spirit, polyoxyethylene castor oil are told in soybean phospholipid, turkey red oil, fatty acid glyceride, poly-fatty acid oil ester, sucrose ester, tween, span, west, polyoxyethylene hydrogenated Oleum Ricini, hot certain herbaceous plants with big flowers acid polyethylene glycol glyceride, oleic acid polyethyleneglycol glyceride, HS15 and composition thereof.

The self-emulsifying drug delivery system requires the diluent can be with the medicine of less consumption dissolving recipe quantity, even under the cryopreservation condition, does not have also that medicine is separated out and easily by the emulsifying agent emulsifying in prescription.Diluent comprises oleic acid, linoleic acid, soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, olive oil, polyglycerol fatty acid fat; hot certain herbaceous plants with big flowers acid glycerol monoesters or dibasic acid esters; hot certain herbaceous plants with big flowers acid glycerol propylene glycol dibasic acid esters; hot certain herbaceous plants with big flowers acid glycerol three esters; acetylated monoglyceride, olein, glyceryl linoleate; the Polyethylene Glycol glyceryl laurate ester, ethyl oleate, isopropyl myristate and composition thereof.

The existing hydrophilic of co-emulsifier has again lipophile, adds co-emulsifier to help to reduce interfacial tension; Increase the mobility of interfacial film; Regulate the HLB value.Reduce again simultaneously the consumption of emulsifying agent, reduce its genotoxic potential.General long-chain alcohol or the long chain acid of using, ethylene glycol, propylene glycol, glycerol, PEG400, hexadecanol, octadecanol, TC and composition thereof all can be used as oral self-emulsifying drug delivery system's cosolvent.

The cyclodextrin that the present invention uses is adsorbent, and adsorbent refers to that adjuvant utilizes self intensive pore to construct to receive liquid, thereby realizes liquid curing.Comprise micropowder silica gel, microcrystalline Cellulose, cyclodextrin, dextrin, calcium hydrogen phosphate, kaolin, magnesium oxide, calcium carbonate, aluminium hydroxide, mannitol, sucrose, arabic gum, pectin, starch, polyvinylpolypyrrolidone and composition thereof.

The poloxamer that the present invention uses is admittedly solidifying agent, admittedly solidifying agent refers to that adjuvant utilizes self solid-liquid dual character, and when high temperature and the liquid drug congruent melting, cooling rear formation waxy solid dispersion, thus realize liquid curing.Comprise Macrogol 4000, polyethylene glycol 6000, hydrogenated vegetable oil, Gelucire 44/14, card pool nurse, poloxamer, glyceryl monostearate, polyglycereol stearate, cocoa butter, Oleum Linderae and composition thereof.

The preparation method of above-mentioned (s)-ibuprofen granules:

Preparation technology: (1) adds isopropyl myristate, polyoxyethylene hydrogenated Oleum Ricini and diethylene glycol ethylether according to the prescription ratio, mix homogeneously gets self-emulsifiable oil substrate; (2) take the (S)-ibuprofen of recipe quantity, add in self-emulsifiable oil substrate, ultrasonic extremely transparent solution obtains (S)-ibuprofen self emulsifying liquid, and ultrasonic time is 20～30min; (3) add cyclodextrin, poloxamer to do carrier in (S)-ibuprofen self emulsifying liquid, put in wet mixing pelletizer, mix 600s, add ethanol and prepare soft material, 24 mesh sieves are granulated, 45～55 ℃ of dryings, 14 mesh sieve granulate, mixing, packing and get final product.

Beneficial effect of the present invention: after adopting the self-emulsifiable oral medicine-releasing system, enter the interior rear (S)-ibuprofen of body and formed nano-particle.Be distributed in equably rapidly digestive system, human body is effectively absorbed, thereby improved human bioavailability, have good economic and social benefit.

One, (S)-ibuprofen raw material research

(S)-ibuprofen is white or off-white color crystallinity powder; Slightly have special smelly.Almost tasteless, easily molten in ethanol, chloroform or ether, dissolve in sodium hydroxide test solution, almost insoluble in water.The fusing point of (S)-ibuprofen is 48～52 ℃.Water solublity is almost insoluble is to affect the key factor that (S)-ibuprofen absorbs.

Two, (s)-ibuprofen granules prescription screening and technical study

The In Vitro Dissolution behavior of domestic granule generally adopts phosphate buffer to measure, covered the situation of the In Vitro Dissolution no better than one ought to of different manufacturers granule, other dosage forms such as tablet etc. adopt the high alkalinity medium to measure the In Vitro Dissolution behavior (pH=7.2) of this product, inconsistent with normal human's physiological environment, indirectly covered the present situation of the In Vitro Dissolution no better than one ought to of different dosage form.The preparation of existing list marketing is all very low at water neutralized salt acid solution dissolution in vitro.For this reason by the solid self-emulsifying technology, adsorb with adsorbent after making (S)-ibuprofen be dissolved in liquid medium, thereby make (S)-ibuprofen form molecular solution, after (S)-ibuprofen self emulsifying granule adds water, form diameter at 100～500nm drop, (S)-ibuprofen is dissolved in drop, forms micellar solution.Therefore the (s)-ibuprofen granules made from the solid self-emulsifying technology, can make in the medium of any pH value and can dissolve, change the In Vitro Dissolution behavior of (S)-ibuprofen, improved the absorbance in the (S)-ibuprofen body, improved the (S)-ibuprofen bioavailability.

Description of drawings

Fig. 1 is embodiment (s)-ibuprofen granules, commercially available capsule and tablet stripping curve figure in water (pH=5.0).

Fig. 2 is embodiment (s)-ibuprofen granules, commercially available capsule and tablet stripping curve figure in hydrochloric acid (pH=1.0).

Fig. 3 is embodiment (s)-ibuprofen granules, commercially available capsule and tablet stripping curve figure in phosphate buffer (pH=7.2).

Fig. 4 is embodiment (s)-ibuprofen granules, commercially available capsule and tablet stripping curve figure in acetate buffer (pH=4.5).

The specific embodiment

Embodiment:

Prescription:

The dissolution of (S)-ibuprofen self emulsifying granule is investigated

(s)-ibuprofen granules and commercially available capsule, the tablet of making carried out dissolution determination.

The dissolution test method:

Get (s)-ibuprofen granules, commercially available capsule and tablet, carry out according to two appendix XC Dissolution Rate Testing the second methods of Chinese Pharmacopoeia version in 2010, respectively take water (pH=5.0), hydrochloric acid solution (pH=1.0), phosphate buffer (pH=7.2), acetate buffer (pH=4.5) 900ml as dissolution medium, rotating speed is per minute 50 to turn, temperature conditions at 37 ± 0.5 ℃, get solution 10ml (adding simultaneously equality of temperature solvent 10ml) during respectively at 5min, 15min, 30min, 45min, 60min, filter, filtrate is as need testing solution; Separately get the (S)-ibuprofen reference substance appropriate, after adding stripping medium ultrasonic dissolution, make the reference substance solution that approximately contains (S)-ibuprofen 160 μ g/ml.According to the method for assay, draw respectively reference substance solution, each 20 μ l injecting chromatographs of need testing solution, record chromatogram, calculate every bag and every bag of cumulated release amount in each time by external standard method, draw each sheet stripping homogeneity figure and stripping curve figure.

Respectively (s)-ibuprofen granules (embodiment, commercially available capsule, tablet) is carried out dissolution determination, result is as follows:

Table 1: (s)-ibuprofen granules, commercially available capsule, tablet stripping curve table in water (pH=5.0)

Time

5min

10min

15min

30min

45min

60min

Embodiment

76.60％

85.70％

92.80％

96.90％

96.40％

95.80％

Commercially available capsule

11.73％

28.72％

43.43％

53.83％

58.77％

66.28％

Tablet

18.52％

31.44％

43.26％

60.36％

64.45％

65.76％

Table 2: (s)-ibuprofen granules, commercially available capsule, tablet stripping curve table in hydrochloric acid solution (pH=1.0)

Time

5min

10min

15min

30min

45min

60min

Embodiment

84.30％

89.50％

95.20％

95.70％

96.30％

95.90％

Commercially available capsule

4.42％

13.53％

24.82％

34.04％

42.74％

54.16％

Tablet

15.59％

26.84％

35.96％

41.06％

45.84％

49.81％

Table 3: (s)-ibuprofen granules, commercially available capsule, tablet stripping curve table in phosphate buffer salt (pH=7.2)

Time

5min

10min

15min

30min

45min

60min

Embodiment

82.60％

90.40％

92.60％

93.40％

95.30％

98.40％

Commercially available capsule

63.88％

92.78％

97.44％

93.86％

99.48％

99.70％

Tablet

71.16％

84.05％

88.72％

89.94％

89.46％

94.10％

Table 4: (s)-ibuprofen granules, commercially available capsule, tablet stripping curve table in acetate buffer (pH=4.5)

Time

5min

10min

15min

30min

45min

60min

Embodiment

93.50％

96.60％

96.80％

97.60％

97.20％

98.70％

Capsule

14.28％

36.46％

62.86％

80.49％

91.89％

98.90％

Tablet

22.27％

36.73％

53.92％

75.78％

81.74％

89.80％

Claims

1. (s)-ibuprofen granules is characterized in that: this granule is a kind of preparation that is prepared into take (S)-ibuprofen as medicinal ingredient and by the solid self-emulsifying technology, and this granule is made by following supplementary material:

This preparation method of granules comprises the following steps: (1) adds isopropyl myristate, polyoxyethylene hydrogenated Oleum Ricini and diethylene glycol ethylether according to the prescription ratio, mix homogeneously gets self-emulsifiable oil substrate; (2) take the (S)-ibuprofen of recipe quantity, add in self-emulsifiable oil substrate, ultrasonic extremely transparent solution obtains (S)-ibuprofen self emulsifying liquid, and ultrasonic time is 20～30min; (3) add cyclodextrin, poloxamer to do carrier in (S)-ibuprofen self emulsifying liquid, put in wet mixing pelletizer, mix 600s, add ethanol and prepare soft material, 24 mesh sieves are granulated, 45～55 ℃ of dryings, 14 mesh sieve granulate, mixing, packing and get final product.