CN102727438B - Repaglinide liposome solid preparation - Google Patents
Repaglinide liposome solid preparation Download PDFInfo
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- CN102727438B CN102727438B CN201210222234.1A CN201210222234A CN102727438B CN 102727438 B CN102727438 B CN 102727438B CN 201210222234 A CN201210222234 A CN 201210222234A CN 102727438 B CN102727438 B CN 102727438B
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Abstract
The invention provides a repaglinide liposome solid preparation, and a preparation method thereof. According to the invention, repaglinide, ovolecithin, soyasterol, and dilauroyl phosphatidyl glycerol with a certain weight ratio are prepared into repaglinide liposome with excellent quality; and the repaglinide liposome is prepared into a solid preparation with a common preparation method. Compared with existing preparations, the preparation provided by the invention is advantaged in substantially improved preparation stability, bioavailability, product quality, and release-retarding effect, and reduced toxic and side effects.
Description
Technical field
The present invention relates to a kind of new solid preparation of antidiabetic medicine repaglinide, be specifically related to a kind of repaglinide lipidosome solid preparation, belong to field of medicine preparations.
Background technology
Repaglinide (Repaglinide) this product is white or off-white color crystalline powder, and odorless is easily molten in chloroform, slightly molten in ethanol or acetone, almost insoluble in water, slightly soluble in 0.1mol/L hydrochloric acid solution.Chemical name is (S+)-2-ethyoxyl-4-[2-[3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl]-amino]-2-carbonyl ethyl benzoic acid, molecular formula C
27h
36n
2o
4, molecular weight: 452.59, structural formula is:
Repaglinide is a kind of new oral hypoglycemic medicine of methyl benzene methanamine benzoic acid family, it is non-sulfonylurea oral hypoglycemic, be used for the treatment of type Ⅱdiabetes mellitus, its mechanism of action is that the specific receptor of repaglinide on beta Cell of islet film is combined, and promotes to close with the ATP sensitive potassium channel of receptor coupling, suppresses potassium ion from β cell drain, cell membrane depolarization, calcium channel is open, and flow of calcium ions promotes insulin secretion.It acts on faster than sulfonylurea, therefore hypoglycemic activity is very fast after the meal.The glucose regulating of taking while dining for first.Maximum advantage is to imitate the physiological secretion of insulin, effectively controls thus postprandial hyperglycemia.
Now take repaglinide as active component, existing several formulations research and development, for example WO0121159 discloses the combination medicine of the medicine of a kind of repaglinide or Nateglinide and other treatment diabetes, for preventing the disease relevant with treating type Ⅱdiabetes mellitus and diabetes.This patent has also been protected the composition and method of making the same of repaglinide and pharmaceutically acceptable carrier, but the pharmaceutical composition onset of its protection is slow, is a worth and area for improvement.
Patent documentation CN101695491A discloses slow releasing preparation of a kind of repaglinide and preparation method thereof, has solved medicine slightly solubility problem although prescription has passed through meticulous screening, and bioavailability, long-time stability are all the places having much room for improvement.
In pharmaceutical carrier induction system, the research of the submicrons such as microemulsion, microsphere, nanoparticle, liposome, pharmacosomes has become very active field in novel pharmaceutical formulation research.Drug encapsulation can be changed in these submicrons to medicine distribution in vivo, increase the abundance of medicine at target organ, thereby improve curative effect, alleviate toxic and side effects.
In targeting drug delivery system, the research of liposome is comparatively extensive, and liposome has good targeting and biocompatibility in vivo.
Liposome (Liposome) is dispersed in water discovery while carrying out electron microscopic observation by British scholar Bangham and Standlish by phospholipid at first.Phospholipid is dispersed in water self-assembling formation multilamellar vesicle, and every layer is all equal bilayers of lipid not; Vesicle central authorities and being separated by water between each layer, bilayer thickness is about 4nm.Afterwards, this bimolecular folliculus with similar biofilm structure was called to liposome.Liposome can be divided into multilamelar liposome and unilamelar liposome.Unilamelar liposome is divided into again small unilamellar vesicle and large unilamellar vesicle.Small unilamellar vesicle is spherical, and size is generally 20-50 nanometer; Large unilamellar vesicle is of a size of micron number magnitude.
The people such as Britain Lai Men in 1971 start liposome for pharmaceutical carrier, Main Function mechanism is that drug powder or solution are wrapped in the water that liposome bilayer lipid membrane seals or are embedded in liposome bilayer lipid membrane, this microgranule has class cellularity, enter the interior principal agent of human body is activated body autoimmune function by reticuloendothelial system phagocytic, and the interior distribution of the body that changes encapsulated medicine, make the drug main will be liver, spleen, in the histoorgan such as lung and bone marrow, put aside, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine.
In recent years, along with the continuous progress of biotechnology, liposome preparation technology gradual perfection, liposome mechanism of action is further illustrated, in addition liposome is applicable to vivo degradation, avirulence and non-immunogenicity, particularly great number tested data proves that liposome can improve Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces the advantages such as drug dose.
As a kind of new medicinal preparation, Liposomal formulation has the following advantages:
(1) there is slow releasing function: active component slowly discharges, delay renal excretion and metabolism, thereby extend action time, improve mass effect;
(2) dissolubility of increase medicine, improves the quality of the pharmaceutical preparations;
(3) there is targeting: the contained medicine of liposome maintains high concentration in liver, spleen reticuloendothelial system internal organs part, thereby plays the effect of medicine organ targeting;
(4) there is the protective effect to active pharmaceutical ingredient.
(5) reduced drug toxicity.
Summary of the invention
In order to form colory repaglinide lipidosome solid preparation, can good compatible with repaglinide it well be sealed and non-leakage filmogen thereby importantly find, to form colory repaglinide liposome, and find the pharmaceutic adjuvant that can form with repaglinide liposome solid preparation.
To achieve these goals, large quantity research and test that the inventor carries out, find the repaglinide of specified weight proportioning, Ovum Gallus domesticus Flavus lecithin, soyasterol and PE can be made repaglinide liposome, wherein, envelop rate as the repaglinide of active constituents of medicine is high, liposome particle diameter is little and be evenly distributed, the retention time significant prolongation of repaglinide in solid preparation in body circulation, slow release effect is obvious, targeting improves, bioavailability improves, curative effect obviously improves, reduce administration number of times, improve and suffered from person's Compliance.
One of object of the present invention, provides a kind of repaglinide liposome, and it is mainly made up of the composition of following weight proportion:
Preferably, the weight ratio of soyasterol and Ovum Gallus domesticus Flavus lecithin is 1:3-1:5, and the weight ratio of soyasterol and PE is 1:1-2:5.
As concrete embodiment, repaglinide liposome of the present invention, prescription is preferably by the composition of following weight proportion to be made:
More preferably, the weight ratio of soyasterol and Ovum Gallus domesticus Flavus lecithin is 1:3-1:5, and the weight ratio of soyasterol and PE is 1:1-4:5.
As the phospholipid that is used to form liposome, it is of a great variety, and conventional have natural phospholipid and a synthetic phospholipid.The inventor is through long-term conscientious research, through a large amount of screening tests, find to adopt general phospholipid and additives be the liposome prepared of film material under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%, stability and envelop rate are not good.The inventor finds the combination of Ovum Gallus domesticus Flavus lecithin, soyasterol and three kinds of materials of PE, best solution stability and the not good problem of envelop rate of liposome, obtain beyond thought preparation effect, thereby superior in quality liposome is provided.
In repaglinide liposome of the present invention, for the repaglinide of 1 weight portion, the consumption of Ovum Gallus domesticus Flavus lecithin is 10-30 weight portion.If the consumption of Ovum Gallus domesticus Flavus lecithin, lower than 10 weight portions, has, a large amount of free repaglinides are not encapsulated, and the drug loading of liposome is low, and stability also can decline; Otherwise, if the consumption of Ovum Gallus domesticus Flavus lecithin, higher than 30 weight portions, also can decline as the envelop rate of the repaglinide of active constituents of medicine to some extent.
In repaglinide liposome of the present invention, soyasterol and PE are for regulating the membrane stability of liposome.
Soyasterol, as a kind of natural product, combines with Ovum Gallus domesticus Flavus lecithin, stops it to be condensed into crystal structure.Mix in Ovum Gallus domesticus Flavus lecithin duplicature, be similar to " buffer agent " and equally play the effect that regulates membrane structure " mobility ".When facing temperature, can make film reduce ordered arrangement, increase mobility; When facing temperature, can increase the ordered arrangement of film, thereby reduce the mobility of film.Can make liposome bi-layer membrane solidify, thereby reduce the generation of free radical, reduce oxidation level, liposome stability is significantly strengthened.
The inventor finds through research, when soyasterol and Ovum Gallus domesticus Flavus lecithin weight ratio are 1:3-1:5, can form the most stable repaglinide liposome.In the time that soyasterol and Ovum Gallus domesticus Flavus lecithin weight ratio are greater than 1:3, repaglinide liposome membrane mobility is too high, and the repaglinide being wrapped in liposome is easy to discharge; In the time that soyasterol and Ovum Gallus domesticus Flavus lecithin weight ratio are less than 1:5, membrane stability reduces, and repaglinide is easy to seepage; In addition, research also finds, in the time that soyasterol and Ovum Gallus domesticus Flavus lecithin weight ratio are 1:3-1:5, the liposome cytotoxicity forming is low.
Research shows, the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of repaglinide liposome of the present invention is high, is to cause one of factor that drug bioavailability is high.
In addition, the inventor studies discovery, in repaglinide liposome of the present invention, for the repaglinide of 1 weight portion, the consumption of Ovum Gallus domesticus Flavus lecithin is 20-24 weight portion, soyasterol is 4-8 weight portion, and when PE 5-8 weight portion, the envelop rate of the repaglinide liposome forming is high.
In repaglinide liposome of the present invention, using PE is the stability for further improving liposome membrane.
Research is found, in the time using the repaglinide, Ovum Gallus domesticus Flavus lecithin, soyasterol of above-mentioned specified quantitative and PE, can obtain colory repaglinide liposome, its envelop rate and stability are all very high, toxicity is low, and rate of release is low, and targeting is high, bioavailability is high, and curative effect increases.
Repaglinide lipidosome solid preparation of the present invention, specification is 0.5mg, 1mg, 2mg.
The preparation method that the invention provides a kind of repaglinide liposome, the method comprises the following steps:
(a) repaglinide is dissolved in appropriate organic solvent;
(b) Ovum Gallus domesticus Flavus lecithin, soyasterol and PE are dissolved in organic solvent, then (a) poured into fast, mix homogeneously, is incubated 30-40 minute at about 40-65 ℃, remove organic solvent with the decompression of rotation vacuum drier again, make liposome;
In the preferred embodiment of repaglinide method for preparing lipidosome of the present invention, step (a) and (b) described in organic solvent be selected from one or more in ethanol, methanol, acetone, ether, chloroform, normal hexane, dichloromethane, the mixed solution of preferred alcohol and chloroform.
By said method, can prepare the little and uniform repaglinide liposome of particle size distribution of granule, its envelop rate is high, and stability is high, is difficult for leaking, and bioavailability is high.
Research finds, the size of liposome is affect that liposome distributes in vivo and the principal element of the time of staying, and the particle diameter of liposome is less, and the interior time of staying of body is longer.The repaglinide liposome particles of preparing by the inventive method is little, and particle size distribution is even, this be its factor that slow, had good sustained release effect of rate of release, bioavailability are high in vivo it
Another object of the present invention is to provide a kind of repaglinide lipidosome solid preparation, and it is made up of repaglinide liposome and other pharmaceutic adjuvants.
In this article, the meaning of term used " other pharmaceutic adjuvants " or " pharmaceutic adjuvant " refers to the medicinal material except repaglinide liposome using in order to prepare repaglinide lipidosome solid preparation, comprises filler, disintegrating agent, binding agent, lubricant and combination thereof.
In this article, term used " amounts of other pharmaceutic adjuvants " refers to the weight sum of above-mentioned pharmaceutic adjuvant.
In a preferred embodiment of repaglinide lipidosome solid preparation of the present invention, described filler is selected from one or more in starch, pregelatinized Starch, lactose, sorbitol, microcrystalline Cellulose, dextrin, mannitol, be preferably the combination of lactose and microcrystalline Cellulose, more preferably the weight ratio of both 1:1.
In a preferred embodiment of repaglinide lipidosome solid preparation of the present invention, disintegrating agent is selected from one or more of low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, crosslinked carboxylic hypromellose sodium, polyvinylpolypyrrolidone, preferably low-substituted hydroxypropyl cellulose.
In a preferred embodiment of repaglinide lipidosome solid preparation of the present invention, described binding agent is selected from one or more in PVP K30, hypromellose, carboxylic hypromellose sodium, arabic gum, xanthan gum, hypromellose and ethyl cellulose, is preferably PVP K30.
In a preferred embodiment of repaglinide lipidosome solid preparation of the present invention, the alcoholic solution that the solvent of wherein said binding agent is 50%.
In a preferred embodiment of repaglinide lipidosome solid preparation of the present invention, lubricant is selected from one or more in magnesium stearate, zinc stearate, Pulvis Talci, Macrogol 4000, stearic acid, is preferably magnesium stearate.
As one of concrete embodiment, repaglinide lipidosome solid preparation of the present invention, mainly divides and makes by following weight portion component:
One of object of the present invention is to provide the preparation method of above-mentioned repaglinide lipidosome solid preparation, and the method comprises the following steps:
(c) repaglinide liposome and filler, disintegrating agent are mixed, the mix homogeneously that sieves, adds binder solution to prepare soft material, the granulation of sieving, and dry, the granulate that sieves must be done granule;
(d), by even to dry granule and mix lubricant, tabletting, makes repaglinide lipidosome solid preparation.
The repaglinide lipidosome solid preparation that the present invention makes, increase the retention time of medicine in body circulation, the bioavailability that has improved medicine, curative effect obviously improves, and reduces administration number of times, improve patient's Compliance, the accumulated dose that reduces medication, so that minimum dose reaches greatest treatment efficacy, has improved the quality of formulation products, reduce toxic and side effects, be more suitable for patient and use.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the blood drug level-time graph of repaglinide lipidosome solid preparation.
Wherein:
The specific embodiment
By concrete preferred embodiment, the present invention is further described below.These embodiment are only illustrative, and should not be construed as limitation of the present invention.
embodiment 1the preparation of repaglinide liposome sheet
Prescription: (1000)
Adopt following production technology to prepare repaglinide liposome sheet:
(1) 0.5g repaglinide is dissolved in the mixed solution of 5ml ethanol and chloroform;
(2) Ovum Gallus domesticus Flavus lecithin 11g, soyasterol 3g and PE 3.25g are dissolved in the mixed solution of 50ml ethanol and chloroform, then (1) is poured into fast, mix homogeneously, 59 ℃ of insulation 30-40 minute, remove organic solvent with the decompression of rotation vacuum drier again, make lipidosome solid;
(3) repaglinide lipidosome solid and 31.95g lactose, 31.95g microcrystalline Cellulose and 5.325g low-substituted hydroxypropyl cellulose are mixed, cross 80 mesh sieve mix homogeneously, add 50% alcoholic solution 50ml of 5% PVP K30 to prepare soft material, cross 24 mesh sieves and granulate, dry;
(4) by dry granule and 1.33g magnesium stearate mix homogeneously, cross 20 mesh sieve granulate, tabletting, makes repaglinide liposome sheet.
embodiment 2the preparation of repaglinide liposome sheet
Prescription: (1000)
Adopt following production technology to prepare repaglinide liposome sheet:
(1) 1g repaglinide is dissolved in the mixed solution of 5ml ethanol and chloroform;
(2) Ovum Gallus domesticus Flavus lecithin 20g, soyasterol 4g and PE 5g are dissolved in the mixed solution of 50ml ethanol and chloroform, then (1) is poured into fast, mix homogeneously, 55 ℃ of insulation 30-40 minute, remove organic solvent with the decompression of rotation vacuum drier again, make lipidosome solid;
(3) repaglinide lipidosome solid and 45g lactose, 45g microcrystalline Cellulose and 6g low-substituted hydroxypropyl cellulose are mixed, cross 80 mesh sieve mix homogeneously, add 50% alcoholic solution 80ml of 5% PVP K30 to prepare soft material, cross 24 mesh sieves and granulate, dry;
(4) by dry granule and 1.5g magnesium stearate mix homogeneously, cross 20 mesh sieve granulate, tabletting, makes repaglinide liposome sheet.
embodiment 3the preparation of repaglinide liposome sheet
Prescription: (1000)
Adopt following production technology to prepare repaglinide liposome sheet:
(1) 2g repaglinide is dissolved in the mixed solution of 10ml ethanol and chloroform;
(2) Ovum Gallus domesticus Flavus lecithin 48g, soyasterol 16g and PE 16g are dissolved in the mixed solution of 100ml ethanol and chloroform, then (1) is poured into fast, mix homogeneously, 60 ℃ of insulation 30-40 minute, remove organic solvent with the decompression of rotation vacuum drier again, make lipidosome solid;
(3) repaglinide lipidosome solid and 174g lactose, 174g microcrystalline Cellulose and 34g low-substituted hydroxypropyl cellulose are mixed, cross 80 mesh sieve mix homogeneously, add 50% alcoholic solution 200ml of 5% PVP K30 to prepare soft material, cross 24 mesh sieves and granulate, dry;
(4) by dry granule and 8g magnesium stearate mix homogeneously, cross 20 mesh sieve granulate, tabletting, makes repaglinide liposome sheet.
comparative example 1-3
As shown in component in following table 1, adopting respectively and 1,2,3 identical production technologies in embodiment, carry out production comparative example 1-3, is all the amount of making 1000 repaglinide liposome sheets:
Composition used in table 1 comparative example 1-3
Wherein, "/" represents not use.
test example 1the investigation of liposome
Lipidosome solid the sample prepared step (2) of embodiment 1-3 and comparative example 1-3 is carried out to quality investigation, mainly carry out liposome morphologic observation, particle size determination and liposome encapsulation and measure.
Wherein, liposome form and particle size determination adopt optical microscopy and the computing of statistica5.0 statistical software to observe approximately 2000 to average;
Entrapment efficiency determination adopts column chromatography for separation in conjunction with spectrophotometry, the method operating procedure is: use column chromatography the liposome in drug solution is separated, utilize surfactant to destroy liposome bilayer, after making drug release out, calculate envelop rate with HPLC method and standard control again, ooze %=(W bag-W by formula Q and store)/W bag × 100% calculating percolation ratio.
The results are shown in following table 2.
The investigation result of table 2 liposome
As shown in Table 2, gained repaglinide liposome form rule in embodiment of the present invention 1-3, size homogeneous, mean diameter is little, and envelop rate is higher, and percolation ratio is low; And gained repaglinide liposome form is irregular in comparative example 1-3, mean diameter is large, and envelop rate is low, and percolation ratio is high.
Particularly, from the result of embodiment and comparative example relatively, when composition beyond the composition that uses the present invention to limit, the quality of gained repaglinide liposome is obviously inferior to the present invention.Even in the time adopting same production technology and component, outside the amount ranges that supplementary material consumption limits in the present invention or outside proportion time, the quality of gained repaglinide liposome is obviously inferior to the present invention.
test example 2stability and dissolution are investigated
Repaglinide lipidosome solid preparation sample prepared by above embodiment 1-3 and comparative example 1-3 and the repaglinide (manufacturer: Jiangsu Haosen Pharmaceutical Co., Ltd of listing, factory site: economic and technological development zone, Lianyun Harbour, Jiangsu Province, lot number: 20101211) 40 ℃ of high temperature, lower 6 months of relative humidity 75% ± 5% condition, carry out accelerated test investigation, the results are shown in following table 3.
Table 3 accelerated test result
As shown in Table 3, the dissolution of listing repaglinide and comparative example 1-3 is low, and while accelerating June, content reduces obviously, and related substance raises; And the sample dissolution of preparing in embodiment of the present invention 1-3 is high, accelerate after 6 months content and related substance all without significant change.Absolutely prove the superiority of the present invention aspect raising stability and dissolution.
test example 3the mensuration of blood drug level
45 rats are divided into 7 groups at random, distinguish gavage embodiment 1-3, comparative example 1-3 and commercially available repaglinide (specification: 1mg for every group, manufacturer: Jiangsu Haosen Pharmaceutical Co., Ltd, factory site: economic and technological development zone, Lianyun Harbour, Jiangsu Province, lot number: 20101211).After administration, respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h, take a blood sample, blood sample after treatment, is measured blood drug level with HPLC-MS method.Make repaglinide lipidosome solid preparation of the present invention and commercially available repaglinide and the average blood drug level of comparative example 1-3 and the relation curve of time, as Fig. 1.
As shown in Figure 1, in the embodiment of the present invention, repaglinide lipidosome solid preparation discharges slowly, reaches good slow release effect, and in comparative example, repaglinide lipidosome solid preparation is poor with the slow release effect of listing preparation.
industrial applicibility
Known according to the result of above-described embodiment and comparative example, repaglinide lipidosome solid preparation of the present invention has good outward appearance, and particle diameter is even, and granule is little, and envelop rate is high, and stability is high, and percolation ratio is low, and bioavailability is high, has good industrial application value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; these explanations do not form any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; we carry out many modifications and replacement to technical solutions and their implementation methods of the present invention; because these all, in protection scope of the present invention, please be understood.
Each list of references of mentioning in the application or quoting, which is hereby incorporated by reference.
Claims (3)
1. a repaglinide liposome, is characterized in that being made up of the composition of following weight proportion:
Wherein, the weight ratio of soyasterol and Ovum Gallus domesticus Flavus lecithin is 1:3-1:5, and the weight ratio of soyasterol and PE is 1:1-2:5,
Its preparation method comprises the following steps:
(a) repaglinide is dissolved in a small amount of organic solvent;
(b) Ovum Gallus domesticus Flavus lecithin, soyasterol and PE are dissolved in organic solvent, then (a) poured into fast, mix homogeneously, is incubated 30-40 minute at 40-65 ℃, remove organic solvent with the decompression of rotation vacuum drier again, make liposome;
Wherein, step (a) and (b) described in organic solvent be the mixed solution of ethanol and chloroform.
2. repaglinide liposome according to claim 1, is characterized in that being made up of the composition of following weight proportion:
Wherein, the weight ratio of soyasterol and Ovum Gallus domesticus Flavus lecithin is 1:3-1:5, and the weight ratio of soyasterol and PE is 1:1-4:5.
3. a repaglinide liposome tablet, is characterized in that being made up of following component by weight:
Wherein, the weight ratio of soyasterol and Ovum Gallus domesticus Flavus lecithin is 1:3-1:5, and the weight ratio of soyasterol and PE is 1:1-4:5.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080233183A1 (en) * | 2007-03-22 | 2008-09-25 | Pathfinder Management, Inc. | Topical formulations having enhanced bioavailability |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080233183A1 (en) * | 2007-03-22 | 2008-09-25 | Pathfinder Management, Inc. | Topical formulations having enhanced bioavailability |
Non-Patent Citations (2)
| Title |
|---|
| 大豆甾醇及其葡萄糖苷对脂质体生物化学性质的影响;陈建明等;《国外医学药学分册》;20010430;第28卷(第2期);97-100 * |
| 陈建明等.大豆甾醇及其葡萄糖苷对脂质体生物化学性质的影响.《国外医学药学分册》.2001,第28卷(第2期),97-100. |
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