CN100563636C - Acemetacin sustained-release preparation and preparation method - Google Patents

Acemetacin sustained-release preparation and preparation method Download PDF

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Publication number
CN100563636C
CN100563636C CNB2007101393188A CN200710139318A CN100563636C CN 100563636 C CN100563636 C CN 100563636C CN B2007101393188 A CNB2007101393188 A CN B2007101393188A CN 200710139318 A CN200710139318 A CN 200710139318A CN 100563636 C CN100563636 C CN 100563636C
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acemetacin
preparation
controlled release
release layer
xanthan gum
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CN101125129A (en
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郭卫芹
张�育
李国聪
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Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
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Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
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Abstract

A kind of Acemetacin sustained-release preparation and preparation method belong to medical technical field, are used to solve the problem that the acemetacin plasma half-life is short, keep therapeutical effect time weak point.It is made of the controlled release layer of acemetacin medicated core and parcel medicated core, and described controlled release layer is made up of xanthan gum-chitosan compound, and wherein, the percentage ratio that xanthan gum content accounts for xanthan gum-chitosan gross weight is 20%~80%.The present invention slows down drug releasing rate in acemetacin medicated core outer wrapping multilamellar controlled release layer by the number of plies or the encapsulation ratio that increases controlled release layer.Test shows that said preparation is compared the release that can be good at controlling medicine with regular dosage form, can keep the blood drug level of therapeutic dose in 24 hours with administering mode once a day.It has overcome the deficiencies in the prior art, provides a kind of and can control the stable release of medicine, prolong drug curative effect for a long time, reduced untoward reaction, does not occur the peroral dosage form of the incomplete phenomenon of drug release basically.

Description

Acemetacin sustained-release preparation and preparation method
Technical field
The present invention relates to a kind of protracted release drug preparation and preparation method thereof, particularly a kind of Acemetacin sustained-release preparation belongs to medical technical field.
Background technology
Acemetacin (Acemetacin), chemical name are 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-second carboxylic acid methyl ester, are nonsteroidal antiinflammatory drug, can be by suppressing synthetic generation antiinflammatory, analgesia, the refrigeration function of prostatitis element.Acemetacin is mainly used in treatment: 1, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis; 2, scapulohumeral periarthritis, bursitis, tendon and tenosynovitis; 3, lumbago and backache, sprain, strain and other soft tissue injurys; 4, acute gout; 5, dysmenorrhea, toothache and postoperative pain.Behind the oral acemetacin, mainly exist in the blood with indomethacin and micro-acemetacin.Acemetacin absorbs half-life 0.86h, eliminates half-life 2.92h, peak time 2.79h, and reaching peak concentration is 1.49 μ g/ml.Metabolite through homaluria reaches more than 99%, and excretory major metabolite is indomethacin, go the chlorobenzene formacyl acemetacin and go the chlorobenzene formacyl indomethacin.Because the acemetacin plasma half-life is shorter, reactive compound is drained or metabolism is fallen after several hours, blood drug level also drops to the level that has been not enough to therapeutical effect thereupon, therefore need to increase amount of drug, promptly increase the number of times of taking medicine every day, but increased thereupon that the patient feels sick, the probability of ill symptomses such as vomiting, stomachache, diarrhoea, inappetence, fecal occult blood (indivedual cases may cause anemia), digestive tract ulcer (sometimes with hemorrhage and perforation), headache, dizzy, drowsiness/fatigue, tinnitus, brought inconvenience to the patient.Therefore, in the clinical practice, press for a kind of medicine of can controlling for a long time and stablize release, prolong drug curative effect, reduce untoward reaction, and can not occur the acemetacin peroral dosage form of the incomplete phenomenon of drug release basically.
Summary of the invention
The present invention be used to overcome prior art defective, provide a kind of and can control stable releases of medicine, prolong drug curative effect, minimizing untoward reaction for a long time, and the acemetacin oral sustained release dosage form and the preparation method of the incomplete phenomenon of drug release can not appear basically.
The alleged problem of the present invention is solved by following technical scheme:
A kind of Acemetacin sustained-release preparation, it is made of the controlled release layer of acemetacin medicated core and parcel medicated core, and described controlled release layer is made up of xanthan gum-chitosan compound, and wherein, the percentage ratio that xanthan gum content accounts for xanthan gum-chitosan gross weight is 20%~80%.
Above-mentioned Acemetacin sustained-release preparation, it is carrier, carrying medicinal active ingredient acemetacin that described acemetacin medicated core adopts the mixture of microcrystalline Cellulose and hydroxypropyl emthylcellulose, wherein, the weight ratio of acemetacin, microcrystalline Cellulose and hydroxypropyl emthylcellulose is 1: 1.5: 0.1.
Above-mentioned Acemetacin sustained-release preparation, the number of plies of described controlled release layer are 1~30 layer, and encapsulation ratio is 4~150% of a medicated core weight.
Above-mentioned Acemetacin sustained-release preparation, the number of plies of described controlled release layer are 4~15 layers, and encapsulation ratio is 10~90% of a medicated core weight.
Above-mentioned Acemetacin sustained-release preparation, described acemetacin medicated core are granule, spherical or miniature lamellar.
A kind of preparation method of Acemetacin sustained-release preparation, it adopts the following steps preparation:
A, formula ratio acemetacin, microcrystalline Cellulose, hydroxypropyl emthylcellulose are mixed, water is mixed well the preparation medicated core;
B, with xanthan gum-chitosan compound 95% alcohol solution-forming, concentration is 50mg/ml, on medicated core, vacuum drying can get the granule of one deck controlled release layer with the coating device spray coating; If preparation multilamellar controlled release layer, then the xanthan gum of reuse different content-chitosan compound solution carries out spray coating once more on the gained coatings, and said process carries out repeatedly, until the Acemetacin sustained-release preparation that obtains required number of plies controlled release layer.
Preparation of the present invention is short at existing acemetacin plasma half-life, pharmaceutical active compounds is drained in human body or metabolism fast, keep short problem of therapeutical effect time improves, the controlled release layer of forming by xanthan gum-chitosan compound in acemetacin medicated core outer wrapping, can control the release of medicine, in addition by increasing the dosage form that the number of plies or encapsulation ratio can obtain different release characteristics.Adopt size, the shape of the preparation of the inventive method preparation, all can reach the purpose of effective control drug release regardless of medicated core.Test shows that the present invention compares the release that can be good at controlling medicine with regular dosage form, can keep the blood drug level of therapeutic dose in 24 hours with administering mode once a day.Take preparation of the present invention and can obtain more smooth blood drug level-time graph, and with every day multiple dosing mutually specific energy control the blood drug level scope of therapeutic dose better.It has overcome the deficiencies in the prior art, provides a kind of and can control the stable release of medicine, prolong drug curative effect for a long time, reduced untoward reaction, has eliminated the incomplete phenomenon of drug release basically.
The specific embodiment
Preparation of the present invention is made of the controlled release layer of acemetacin medicated core and parcel medicated core, and wherein controlled release layer is made up of xanthan gum-chitosan compound.Encapsulation ratio (encapsulation ratio: controlled release layer is with respect to the % weight of medicated core) that the present invention can be by increasing controlled release layer or the encapsulation ratio of keeping every layer of controlled release layer are constant, and the number of plies that increases controlled release layer is regulated the rate of release of medicine, to reach different release characteristics.Therefore regardless of size, the shape of medicated core, use xanthan gum of the present invention-chitosan compound packaging medicine all can reach the purpose of effective control drug release.The physicochemical properties of physicochemical property, xanthan gum and the chitosan of the present invention by investigating acemetacin etc. have been determined the number of plies, the encapsulation ratio of controlled release layer, to obtain required drug release parameter.The number of plies of controlled release layer is 1~30 layer, and encapsulation ratio is 4~150% weight, 4~15 layers of the preferred numbers of plies, and encapsulation ratio is 10~90% weight.Wherein when controlled release layer be more than 2 layers the time, be object of reference with the content of xanthan gum in the multilamellar controlled release layer, this multilamellar controlled release layer is by being close to drug core layer to away from drug core layer, the content of yellow source glue can successively decrease, can increase progressively, can subtract afterwards earlier and increase, increase afterwards earlier and subtract, also can present irregularities and distribute.
Acemetacin sustained-release preparation among the present invention can further be made peroral dosage form with other active component, pharmaceutical excipient.Described other active agent preparations comprise other formulations of active ingredients that synergistic therapeutic action is arranged with acemetacin on other preparations of acemetacin such as quick releasing formulation, the pharmacology.Conventional pharmaceutic adjuvants such as described pharmaceutical excipient such as disintegrating agent, diluent, lubricant, adhesive.
The acemetacin immediate release section is by medicinal active ingredient acemetacin and conventional pharmaceutic adjuvant; as compositions such as disintegrating agent, diluent, lubricant, adhesive; the consumption of pharmaceutic adjuvant determines that according to the consumption of principal agent acemetacin compound method can adopt methods such as wet granulation, dry granulation, lamination granulation or impregnation granulation.
Described peroral dosage form can be the conventional peroral dosage forms of pharmaceutical fields such as capsule, tablet.
According to " Chinese Pharmacopoeia 2005 editions " two appendix XC dissolution method second methods the dissolution in vitro of preparation of the present invention and conventional formulation has been carried out investigating contrast.Dissolution test is under 37 ℃, carry out in 900ml0.05M, pH value are 6.8 phosphate buffer with preparation, uses high performance liquid chromatograph to detect.Use the optical fiber dissolution system, to the second dervative correction method of 289nm scope rate of release carried out in site measurement at 283nm with wave-length coverage, dissolution parameters following (percent of mentioning below is percentage by weight):
Preparation conventional formulation of the present invention
About 7% acemetacin discharges about 30% acemetacin release after 1 hour
About 20% acemetacin discharges about 55% acemetacin release after 2 hours
About 35% acemetacin discharges about 85% acemetacin release after 4 hours
About 60% acemetacin discharges about 90% acemetacin release after 8 hours
About 85% acemetacin discharges about 95% acemetacin release after 12 hours
About 90% acemetacin discharges after 18 hours
About 93% acemetacin discharges after 24 hours
As seen preparation of the present invention can be good at controlling the release of medicine.Preparation of the present invention can keep the blood drug level of therapeutic dose with administering mode once a day in 24 hours, obtain more smooth blood drug level-time graph, and with every day multiple dosing mutually specific energy control the blood drug level scope of therapeutic dose better.In other words, the invention provides peak valley appears in a kind of reduction because of the blood drug level of repeatedly taking conventional acemetacin dosage form every day and causing method.Test shows, the plasma concentration of preparation of the present invention acemetacin in about 5~8 hours raises, and the residue during 24 hours begins to be close to linear decline at leisure then, but has kept the critical treatment concentration of medicine between whole 24 hours at least.In contrast, plasma peaks promptly appearred in conventional acemetacin preparation in 2~3 hours.Therefore the present invention has overcome the deficiencies in the prior art, provides a kind of and can control the stable release of medicine, prolong drug curative effect for a long time, reduced untoward reaction, and can not occur the acemetacin peroral dosage form of the incomplete phenomenon of drug release basically.
Below provide several specific embodiments:
1000/sheet of embodiment 1-6 preparation Acemetacin sustained-release dosage form
Medicated core is formed:
Embodiment 123456
Acemetacin 70g 80g 90g 100g 110g 120g
Microcrystalline Cellulose 105g 120g 135g 150g 165 180g
Hydroxypropyl emthylcellulose 7g 8g 9g 10g 11g 12g
Controlled release layer is formed:
Form 1 30% xanthan gum, 70% chitosan;
Form 2 40% xanthan gum, 60% chitosan;
Form 3 50% xanthan gum, 50% chitosan;
Form 4 60% xanthan gum, 40% chitosan;
Form 5 70% xanthan gum, 30% chitosan;
Form 6 80% xanthan gum, 20% chitosan.
Above-mentioned controlled release layer is mixed with solution with 95% ethanol when spray coating.
Preparation method:
Arbitrary medicated core is formed the controlled release layer that all can select the different proportionings of above-mentioned multilamellar in the embodiment of the invention, contains the different xanthan gum-chitosan of consumption each other as long as satisfy adjacent two layers.
A, prepare difform medicated core:
Get acemetacin, microcrystalline Cellulose, the hydroxypropyl emthylcellulose of arbitrary formula ratio and mix well with suitable quantity of water, gained colloid group is by extruding, spheronizing medicated core.Granulate and also can adopt high speed shear formula granulator, in exsiccator, carry out drying, granulate then; Perhaps behind drying, granulate, add lubricant,, be pressed into miniature small pieces with tablet machine as magnesium stearate.
B, parcel controlled release layer:
Weight according to medicated core, determine total encapsulation ratio of multilamellar controlled release layer, the number of plies that will wrap up according to desire is determined every layer encapsulation ratio again, use the fluidized coating device, the controlled release layer of under fluidized state arbitrary xanthan gum of the present invention-chitosan being formed is carried out spray coating on spherical medicated core, graininess medicated core or miniature lamellar medicated core, the controlled release layer of forming with the different xanthan gum with this layer coatings of content-chitosan on the gained coatings is carried out coating once more, carries out this step repeatedly and can arrive required multilamellar controlled release layer.
With embodiment 1 is that example describes:
Get acemetacin 70g, microcrystalline Cellulose 105g, hydroxypropyl emthylcellulose 7g, mix well with suitable quantity of water, gained colloid group is by extruding, spheronizing medicated core;
Medicated core weight is that 182g is in 4~150% scopes at 1~30 layer of controlled release layer of the present invention, encapsulation ratio, can select to arrange in pairs or groups as follows for reaching releasing effect:
Every layer of encapsulation ratio of total encapsulation ratio parcel number of plies
4% 2 2%
10% 4 2.5%
40% 4 10%
50% 15 0%
60% 10 6%
75% 15 5%
90% 16 5.6%
120% 30 4%
150% 10 15%
Acemetacin medicated core among the embodiment 1 is carried out the controlled release layer parcel, is that total encapsulation ratio is 60% as the parcel condition, wraps up 10 layers, and then average every layer of encapsulation ratio is 6%:
Carry out fluidized coating as ground floor with 30% xanthan gum, 70% chitosan alcoholic solution (xanthan gum 3.276g, chitosan 7.644g);
The second layer carries out fluidized coating with 50% xanthan gum, 50% chitosan alcoholic solution (xanthan gum 5.46g, chitosan 5.46g) on the basis of ground floor coating;
The xanthan gum of the 3rd layer of usefulness 60%, 40% chitosan alcoholic solution (xanthan gum 6.552g, chitosan 4.368g) carry out fluidized coating on the basis of second layer coating;
The xanthan gum of the 4th layer of usefulness 50%, 50% chitosan alcoholic solution (xanthan gum 5.46g, chitosan 5.46g) carry out fluidized coating on the basis of the 3rd layer of coating;
Layer 5 carries out fluidized coating with 45% xanthan gum, 55% chitosan alcoholic solution (xanthan gum 4.914g, chitosan 6.006g) on the basis of the 4th layer of coating;
Layer 6 carries out fluidized coating with 40% xanthan gum, 60% chitosan alcoholic solution (xanthan gum 4.368g, chitosan 6.552g) on the basis of layer 5 coating;
Layer 7 carries out fluidized coating with 80% xanthan gum, 20% chitosan alcoholic solution (xanthan gum 8.736g, chitosan 2.184g) on the basis of layer 6 coating;
Layer 7 carries out fluidized coating with 70% xanthan gum, 30% chitosan alcoholic solution (xanthan gum 7.644g, chitosan 3.276g) on the basis of layer 6 coating;
The xanthan gum of the 8th layer of usefulness 40%, 60% chitosan alcoholic solution (xanthan gum 4.368g, chitosan 6.552g) carry out fluidized coating on the basis of layer 7 coating;
The xanthan gum of the 9th layer of usefulness 65%, 35% chitosan alcoholic solution (xanthan gum 7.098g, chitosan 3.822g) carry out fluidized coating on the basis of the 8th layer of coating;
The xanthan gum of the tenth layer of usefulness 45%, 55% chitosan alcoholic solution (xanthan gum 4.914g, chitosan 6.006g) carry out fluidized coating on the basis of the 9th layer of coating;
The medicated core of this parcel controlled release layer mixed incapsulating with magnesium stearate, or with magnesium stearate, little silicon dioxide colloid mixed pressuring plate.
Embodiment 7: preparation contains the Acemetacin sustained-release dosage form of the dual medicine-releasing system of Acemetacin sustained-release preparation of the present invention and acemetacin quick releasing formulation
Acemetacin rapid release release preparation prescription
Acemetacin 30g cane sugar powder 40g micropowder silica gel 0.75g 50% ethanol is an amount of
Acemetacin rapid release release formulation preparation method
Take by weighing acemetacin, cane sugar powder, micropowder silica gel mix homogeneously, add 50% ethanol and granulate in right amount, 60 ± 5 ℃ of dryings, it is standby to get between the 20-40 order granule;
The preparation of the dual medicine-releasing system preparation of acemetacin
Take by weighing acemetacin quick releasing formulation and slow releasing preparation of the present invention, add magnesium stearate, mix homogeneously incapsulates or tabletting.
A comparison example below is provided: acemetacin blood drug level (μ g/ml) is the contrast of conventional formulation and slow releasing preparation of the present invention over time
Following table is that initial blood drug level is 0 male patient's blood drug level of acemetacin and the ratio of time, and the lineup takes the conventional formulation of 90mg, and the lineup takes the preparation of the present invention of 90mg in addition:
Initial blood drug level is the blood drug level of 0 acemetacin
Time (hour) 1 * 90mg conventional formulation, 1 * 90mg preparation of the present invention
0 0 0
1 0.87 0.23
1.5 1.12 0.47
3 1.37 0.82
4 1.31 0.94
6 1.29 1.49
8 1.17 1.46
10 1.08 1.41
12 0.92 1.33
14 0.86 1.28
16 0.81 1.21
20 0.72 1.18
24 0.65 1.07
28 0.54 0.91
36 0.43 0.87
48 0.21 0.63
The result shows, reaches acemetacin blood drug level peak value after the Acemetacin sustained-release preparation administration of the present invention in 6 hours.And the patient who takes conventional formulation just reached the blood drug level peak value in about 3 hours.Acemetacin sustained-release preparation of the present invention the blood drug level peak valley phenomenon that conventional formulation occurs can not occur during the administration of interval after the administration in 24 hours of interval.
For Acemetacin sustained-release preparation of the present invention, because the formation difference of controlled release layer, can show different release characteristics is dropout value, therefore, and can be according to the difference of release characteristics and dropout value, dosage, formulate corresponding instructions of taking, as taking weekly 1 time, each 270mg, took 1 time in per 24 hours, each 180mg, took 1 time in per 12 hours, each 90mg, or the like.
Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be qualification to embodiment of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description, can't give exhaustive here all embodiments.And these belong to variation or the change that basic preparation principle of the present invention extended out and still are among protection scope of the present invention.

Claims (6)

1. Acemetacin sustained-release preparation, it is characterized in that: it is made of the controlled release layer of acemetacin medicated core and parcel medicated core, described controlled release layer is made up of xanthan gum-chitosan compound, and wherein, the percentage ratio that xanthan gum content accounts for xanthan gum-chitosan gross weight is 20%~80%; Described controlled release layer weight is 4~150% of medicated core weight.
2. Acemetacin sustained-release preparation according to claim 1, it is characterized in that: described acemetacin medicated core is that the mixture with microcrystalline Cellulose and hydroxypropyl emthylcellulose is a carrier carrying medicinal active ingredient acemetacin, wherein, the ratio of acemetacin, microcrystalline Cellulose and hydroxypropyl emthylcellulose is 1: 1.5: 0.1 by weight.
3. Acemetacin sustained-release preparation according to claim 2 is characterized in that: the number of plies of described controlled release layer is 1~30 layer.
4. Acemetacin sustained-release preparation according to claim 3 is characterized in that: the number of plies of described controlled release layer is 4~15 layers, and controlled release layer weight is 10~90% of medicated core weight.
5. according to the described Acemetacin sustained-release preparation of claim 4, it is characterized in that: described acemetacin medicated core is granule, spherical, miniature lamellar.
6. method for preparing as Acemetacin sustained-release preparation as described in the claim 1,2,3,4 or 5 is characterized in that it adopts following steps:
A, described formula ratio acemetacin, microcrystalline Cellulose, hydroxypropyl emthylcellulose are mixed, water is mixed well the preparation medicated core;
B, xanthan gum-chitosan compound is mixed with solution with 95% ethanol, on prepared medicated core, behind the vacuum drying, can has the granule of one deck controlled release layer with the coating device spray coating; If preparation multilamellar controlled release layer, then the xanthan gum of reuse different content-chitosan compound solution carries out spray coating on the gained coatings, and said process carries out repeatedly, until the Acemetacin sustained-release preparation that obtains required number of plies controlled release layer.
CNB2007101393188A 2007-08-31 2007-08-31 Acemetacin sustained-release preparation and preparation method Active CN100563636C (en)

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CN106106888A (en) * 2016-06-30 2016-11-16 贵州黔韵福生态茶业有限公司 The processing method of bulk postfermented tea
EP3796904B1 (en) 2018-11-16 2023-01-25 Santa Farma Ilaç Sanayi A.S. Sustained release acemetacin compositions

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