CN1448132A - Modified antineoplastic preparation based on Paclitaxel - Google Patents
Modified antineoplastic preparation based on Paclitaxel Download PDFInfo
- Publication number
- CN1448132A CN1448132A CN03108362A CN03108362A CN1448132A CN 1448132 A CN1448132 A CN 1448132A CN 03108362 A CN03108362 A CN 03108362A CN 03108362 A CN03108362 A CN 03108362A CN 1448132 A CN1448132 A CN 1448132A
- Authority
- CN
- China
- Prior art keywords
- paclitaxel
- preparation
- powder
- mixture
- injectable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A nano-particles antitumor preparation is based on paclitaxel and human serum albumin. The preparation is produced by adding biocompatible acid into albumin solution before mixing the albumin solution and paclitaxel when preparing the nano-particles. The pH value of the preparation is 5.4-5.8, and is stability.
Description
Technical field
The present invention relates to based on paclitaxel and the particulate anti-tumor agent of albumin nanometer, it can produce has the very high not injectable recasting aqueous mixture of change property in time.
Background technology
Paclitaxel is known in the literature natural materials, has important anti-tumor activity.Its weak water solublity makes it be difficult to the administration to the people, owing to this reason, has developed and multiplely can make its injectable system.
Bristol Myers Squibb (BMS) has designed a kind of compositions, and obtained patent, its title is TAXOL , in this compositions, (cremophor) makes paclitaxel emulsifying with cremophor, can make patient produce multiple side effect (Lorenz etc., drug effect (Agents Action) 7,63-67 (1987) like this; Weiss etc., J.Clin.Onc0l.8,1263 (1990)).Because the dilution of active component, BMS preparation also relate to the long problem of administration time.
In order to overcome described shortcoming; BMS is to paclitaxel that same dosage is arranged but use the TAXOL preparation of other excipient that can avoid strong anaphylactic reaction to carry out patent protection (EP-A-0584001, EP-A-0783885, EP-A-0783886; US 5641803, US5670537).Yet, in all cases, must be very lentamente to patient's administration, above about 3 hours.
For preventing the side effect of TAXOL , in view of human serum albumin's (HSA) biocompatibility and very strong and the bonded ability of paclitaxel, replace cremophor (Kumar etc., Res.Comm.in Chem.Path.and Pharm. with it, 80 (3), 337-343 (1993); Paal etc., Eur.J.Biochem.268,2187-2191 (2001)).HSA forms character (Kramer etc., J.Pharm.Sci.63, the 1646-1647 (1974) that contains the microsphere that is dissolved in the active component in the water-insoluble organic solvents; Grinstaff and Suslick, J.Am.Chem.Soc.112,7807-7809 (1990); Grinstaff and Suslick, Polym.Prepr.32,255-256 (1991)), also make exploitation become possibility with the system of the concentration administration paclitaxel that is higher than TAXOL .
Can obtain the injectable nano-emulsion of paclitaxel and HSA by known ultrasound wave, high pressure homogenize and Micro Fluid technology.
Based on these key elements, and by using above-mentioned ultrasound wave, high pressure homogenize technology, U.S. VivoRx pharmaceutical companies has been developed the formulation C APXOL that contains paclitaxel and HSA
(R)
In US 5439686, US 5498421, US 5560933 and corresponding WO94/18954, VivoRx is claimed with the paclitaxel of ultrasonic technology preparation and the microgranule of HSA, obtains the granule of mean diameter (MPS)＜10 micron.The preparation method of putting down in writing in these patents can not be used for industrially scalable, and the microgranule that so obtains has too high MPS, and this is unsuitable for it and can not be used for the administration to patient.
VivoRx knows this point very much; therefore it put down in writing in US 5916596 and US 6096331 and WO 98/14174 and WO 99/00113 and the claimed aseptic nano-emulsion that obtains by the lyophilization powder of remake with aseptic 0.9%NaCl aqueous solution paclitaxel and HSA, its MPS＜0.2 micron.As the patent of quoting as proof is described, these nano-emulsioies that obtain with the high pressure homogenizing method it is said high stability, the meaning of term " stability " had both represented that MPS did not change in time herein, and nanoparticle precipitate (US6096331, embodiment 11) does not appear in expression yet.
With the carefulness of maximum, the inventor has many times repeated the embodiment of aforementioned patent, the embodiment 1,5 and 6 of US 5916596 particularly, the result who illustrates in the embodiment that never obtains in this patent and claims.The inventor has prepared the mixture of being put down in writing, in the pressure limit that US 5916596 recommends, it is handled then with the Avestin homogenizer, obtain the nano-emulsion of pH=6.7, when patent report as described, when evaporation desolventizes in rotary evaporator, total nano-particle that produces about 0.2 micron of MPS (increase＞0.02 of evaporation back MPS micron), (increase of MPS is about 0.05 micron to the preparation instability that they form in injectable physiological solution, in about 12 hours, tend to deposition), and be difficult to filter and sterilize by 0.22 micron filter, this with described patent in claim different.
The applicant is paid to go out maximum patient effort and filters with the film with US 5916596 records, but these results always fail, and causes filter obstruction and taxol yield always to be lower than 30%, different with the 70-100% that claims.In addition, with the preparation of the method just described, never reach 24 hours (so be less than greatly in patent disclosed 72 hours) by the stability of the product of US 5916596 and US 6096331 reported method lyophilizations and recasting (by the technology assessment of the embodiment 11 of US 6096331) then.
Summary of the invention
Main purpose of the present invention provides a kind of anti-tumor agent that is made of paclitaxel and human serum albumin's nano-particle, it can reassemble into injectable mixture with physiological solution, described granule has remarkable in possible in the prior art stability therein, particularly surpasses 24 hours stability.
The preparation that constitutes by the lyophilization powder by paclitaxel and human serum albumin's nano-particle has reached this purpose and further purpose, the amount of paclitaxel is between 1%-20% in preparation, albuminous amount is between 60%-98%, percent is by weight, the mean diameter of nano-particle is less than 0.2 micron, it is characterized in that described cryodesiccated powder contains the biocompatibility salt between the 1%-20% weight, this salt is by at least a biocompatible acid salify or owing to existing the acid buffer substance of at least a biocompatibility to obtain, and the amount of the existence of acid or acidic buffer material is to make the pH of the aqueous injectable mixture that the powder recasting forms between 5.4 and 5.8.
The existence of salt be since acid and salt formation thereof acidic buffer material (known) as the chemist, therefore and some basic groups in the albumin and sour salify have obtained the mixture that its pH is lower than albuminous typical pH (promptly being recited as 6.79-6.89 for 13 editions the 1519th page according to the Merck index).
Experiment has shown that if use acidic buffer material (for example mixture of citric acid and sodium citrate) aspect aforementioned stable, the result is not as only using acid good (citric acid or other biocompatible acid).
Obviously, after adding entry and forming aqueous mixture, can easily measure the pH of lyophilization powder with the lyophilization powder.Research show, also have water in the acidity nanometer granule: in the powder amount of water paramount be 5% (W/W), about usually 2%-4.5% (W/W).Therefore, the above-mentioned nano-particle that contains water has also formed a part of the present invention.
The invention still further relates to the injectable reorganization aqueous mixture of this preparation, wherein, the concentration of paclitaxel between 0.1-3mg/ml, preferred 0.5-2.5mg/m1.
Also can mix with the sterile solution of paclitaxel by aseptic aqueous solution with human serum albumin (HSA), and handle this mixture by the instruction of aforementioned Vivorx patent, obtain preparation of the present invention, but be with the difference of these instructions, with before paclitaxel mixes, add at least a biocompatible acid or acidic buffer material in the aqueous solution of HSA, its addition is enough to pH regulator with solution to 5.4-5.8, preferably between the 5.5-5.7.
Biocompatible acid can be selected from hydrochloric acid, citric acid, phosphoric acid, acetic acid, the acid of biocompatibility organic or inorganic.
Also can obtain same preparation by the following method: 0 ℃-40 ℃ contain paclitaxel and albuminous aqueous mixture are handled through homogeneity under the high pressure of 9000-40000psi, obtain nano-emulsion, it is freezing between-20 ℃ and-80 ℃, and finally+20 ℃ and+heat lyophilizing under the temperature between 35 ℃, under aseptic condition by albumin being dissolved in the concentration that reaches 2%-3% (W/V) in the sterilized water, the chloroform that in this solution, adds 2%-4% (V/V) then, add then and account for albumin weight 5.40%-15.0% in the solution, the paclitaxel of the aseptic powder powder of preferred 5.60%-13.7%, before adding paclitaxel, in described albumin solution, add at least a biocompatible acid of q.s or acidic buffer material with the pH regulator of mixture to 5.4-5.8, between the preferred 5.5-5.7, to obtain described aqueous mixture.
What can notice is: use the paclitaxel of aseptic powder powder not only to simplify flow process itself greatly in one method of back, also make the method can be compared with prior art, the required time of mixing of finishing various components before homogenize is handled is shortened greatly, and also can obtain better ultimate yield, and simplified to obtaining the condition that required aseptic lyophilization powder is followed.
With the result who obtains according to preparation of the present invention is fully unexpected and wonderful because they with prior art for using owing to diluting pH value that the albumin Injectable solution that meets the FDA standard produces at the instruction that the HSA of pH=6.9 ± 0.5 solution provides different (seeing the embodiment 1,5 and 6 of US 5916596).Different with the instruction of prior art is that when having found that pH value is between 5.4 and 5.8, the lyophilisation product for reorganization can obtain the stability greater than 24 hours.
The specific embodiment
For illustrating understanding, the embodiment of some indefinitenesses of its enforcement is described now to feature of the present invention.
Embodiment 1
Prepare preparation with HCl with the paclitaxel that is dissolved in the chloroform
Injectable 25% (w/v) the HSA aqueous solution (pH=6.9 ± 0.5) that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), uses 1M HCl with its pH regulator to 5.6, some the basic group salify in HCl and the albumin.The described solution that 40ml is sterilized in advance mixes with the chloroform sterile solution (59.0mg/ml) of 1.2ml paclitaxel, under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handles until obtaining nano-emulsion (MPS＜0.2 micron) with mixture then, it is freezing to-25 ℃ under aseptic condition, and lyophilizing 60 hours, be warming up to simultaneously+20 ℃.
With the powder that contains 4.25% (W/W) paclitaxel and 3.6% (w/w) water that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2mg/ml.The preparation that obtains has 0.16 micron MPS, pH=5.6, stability＞24 hours.
Replace hydrochloric acid to obtain same result with phosphoric acid.
Embodiment 2
Prepare preparation with citric acid and the paclitaxel that is dissolved in the chloroform
Injectable 25% (w/v) the HSA aqueous solution (pH=6.9 ± 0.5) that will meet the FDA standard with sterile demineralized water is diluted to 2.5% (w/v), with aseptic citric acid with its pH regulator to 5.5, some the basic group salify in citric acid and the albumin.With described solution of 60ml and 1.7ml concentration is that the chloroform sterile solution of the paclitaxel of 60.0mg/ml mixes, under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handles until obtaining nano-emulsion (MPS＜0.2 micron) with mixture then, it is freezing rapidly to-40 ℃ under aseptic condition, and lyophilizing 55 hours, be warming up to simultaneously+35 ℃.
With the powder that contains 5.2% (W/W) paclitaxel and 4.9% (w/w) water that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2mg/ml.The preparation that obtains has 0.17 micron MPS, pH=5.5, stability＞24 hours.
Embodiment 3
Prepare preparation with hydrochloric acid and the paclitaxel that is dissolved in the chloroform
Injectable 25% (w/v) HSA aqueous solution that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), uses 1M HCl with its pH regulator to 5.6, some the basic group salify in hydrochloric acid and the albumin.With described solution of 60ml and 1.5ml concentration is that the chloroform sterile solution of the paclitaxel of 75mg/ml mixes, under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handles until obtaining nano-emulsion (MPS＜0.2 micron) with mixture then, it is freezing rapidly to-50 ℃ under aseptic condition, and lyophilizing 50 hours, be warming up to simultaneously+30 ℃.
With the powder that contains 4.41% (W/W) paclitaxel and 3.8% water that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2.5mg/ml.The preparation that obtains has 0.175 micron MPS, pH=5.6, stability＞24 hours.
By repeating same process but do not add hydrochloric acid, thereby carry out, obtain 0.24 micron MPS and the about 10 hours preparation of stability at about pH6.5.
Embodiment 4
Prepare preparation with citric acid from paclitaxel solution
Injectable 25% (w/v) HSA aqueous solution that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), with citric acid with its pH regulator to 5.4, some the basic group salify in citric acid and the albumin.
Under brute force stirs, the described solution of 50ml was mixed 40 minutes with the chloroform sterile solution (75mg/ml) of 1.25ml paclitaxel at least.。
With mixture under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handle until obtaining nano-emulsion (MPS＜0.2 micron), it is freezing rapidly to-30 ℃ under aseptic condition, and lyophilizing 57 hours, be warming up to simultaneously+35 ℃.
With the powder that contains 5.00% (W/W) paclitaxel and 4.3% (w/w) water that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2mg/ml.The preparation that obtains has 0.19 micron MPS, pH=5.4, stability＞24 hours.
Replace citric acid to obtain same result with acetic acid.
Embodiment 5
Prepare preparation with hydrochloric acid and pulverous paclitaxel
Injectable 25% (w/v) the HSA aqueous solution (pH=6.9 ± 0.5) that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), uses 1M hydrochloric acid with its pH regulator to 5.6, some the basic group salify in hydrochloric acid and the albumin.
With the described solution of 57ml of sterilization in advance, under stirring, brute force, and mixed at least 30 minutes with the pulverous aseptic paclitaxel of 108mg (tire＞99%) with the 1.40ml chloroform.
With mixture under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handle until obtaining nano-emulsion (MPS＜0.2 micron), it is freezing rapidly to-80 ℃ under aseptic condition, and lyophilizing 55 hours, be warming up to simultaneously+30 ℃.
With the powder that contains 4.83% (W/W) paclitaxel and 4% (w/w) water that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2mg/ml.The preparation that obtains has 0.175 micron MPS, pH=5.6, stability＞24 hours.
Replace hydrochloric acid to obtain same result with phosphoric acid.
Be important to note that with pulverous aseptic paclitaxel and can realize important advantage: only need a kind of reactor to form the liquid mixture that contains HSA and paclitaxel, finish essential cost of this technology and time and reduce.
Embodiment 6
Prepare preparation with citric acid and pulverous paclitaxel
Injectable 25% (w/v) HSA aqueous solution that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), with citric acid with its pH regulator to 5.4, some the basic group salify in citric acid and the albumin.
With the described solution of 50ml of sterilization in advance, under stirring, brute force, and mixed at least 40 minutes with the pulverous aseptic paclitaxel of 98mg (tire＞99%) with the aseptic chloroform of 1.23ml.
With mixture under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handle until obtaining nano-emulsion (MPS＜0.2 micron), it is freezing rapidly to-30 ℃ under aseptic condition, and lyophilizing 57 hours, be warming up to simultaneously+35 ℃.
With the powder that contains 4.80% (W/W) paclitaxel and 3.8% (w/w) water that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2mg/ml.The preparation that obtains has 0.19 micron MPS, pH=5.4, stability＞24 hours.
Replace citric acid to obtain same result with acetic acid.
Embodiment 7
Prepare preparation with aseptic citric acid and pulverous paclitaxel
Injectable 25% (w/v) HSA aqueous solution that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), with citric acid with its pH regulator to 5.5, some the basic group salify in citric acid and the albumin.
With the described solution of 37ml, under stirring, brute force mixed at least 40 minutes with the aseptic chloroform of 0.91ml and the pulverous aseptic paclitaxel of 71mg (tire＞99%), mixture is cooled to 5-8 ℃ then.
With mixture under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handle until obtaining nano-emulsion (MPS＜0.2 micron), it is freezing rapidly to-80 ℃ under aseptic condition, and lyophilizing 58 hours, be warming up to simultaneously+30 ℃.
With the powder that contains 4.70% (W/W) paclitaxel and 4.5% (w/w) water that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2mg/ml.The preparation that obtains has 0.185 micron MPS, pH=5.5, stability＞24 hours.
Embodiment 8
Preparation contains the preparation of 9.36% paclitaxel
Injectable 25% (w/v) HSA aqueous solution that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), uses lM hydrochloric acid with its pH regulator to 5.6, some the basic group salify in hydrochloric acid and the albumin.The described solution of 60ml is suitably sterilized, under brute force stirs, be that the paclitaxel chloroform sterile solution of 110mg/ml mixes with 2.15ml concentration, under high pressure (9000-40000psi) in homogenizer (suitably sterilization) handles until obtaining nano-emulsion (MPS＜0.2 micron) with mixture then, it is freezing rapidly to-50 ℃ under aseptic condition, and lyophilizing 50 hours, be warming up to simultaneously+30 ℃.
It is the solution of 2.5mg/ml that the powder that contains 9.36% paclitaxel and 3.9% (W/W) water that obtains is formed paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution again.The preparation that obtains has 0.175 micron MPS, pH=5.6, stability＞24 hours.
Embodiment 9
The preparation of preparation pH5.5
Injectable 20% (w/v) the HSA aqueous solution (pH=6.9 ± 0.5) that will meet the FDA standard with sterile demineralized water is diluted to 3% (w/v), with citric acid with its pH regulator to 5.5, some the basic group salify in citric acid and the albumin.
With the described solution of 110ml, under stirring, brute force mixes with the aseptic chloroform of 4.10ml and the pulverous aseptic paclitaxel of 639mg (tire＞99%), then mixture (suitably sterilization) in the high pressure homogenizer is handled until obtaining nano-emulsion (about 0.2 micron of MPS), vacuum evaporation removes desolvates, freezing and lyophilizing 48 hours.
With the powder that contains 10.8% (W/W) paclitaxel that obtains, forming paclitaxel concentration with the recasting of 0.9%NaCl aqueous solution is the solution of 2mg/ml.The preparation that obtains has 0.15 micron MPS, stability＞24 hours.
Claims (7)
1. the anti-tumor agent of the lyophilization powder of a nano-particle that contains paclitaxel and human serum albumin, wherein the amount of paclitaxel is between 1%-20%, albuminous amount is between 60%-98%, percent is by weight, the mean diameter of nano-particle is less than 0.2 micron, it is characterized in that described cryodesiccated powder contain between the 1%-20% weight biocompatibility salt, it is by at least a biocompatible acid salify or owing to existing at least a biocompatible acid buffer substance to obtain, and the amount that acid or acidic buffer material exist is to make the pH of the injectable aqueous mixture that the powder recasting forms between 5.4 and 5.8.
2. the described preparation of claim 1 is characterized in that described pH is between 5.5 and 5.7.
3. claim 1 and 2 described preparations is characterized in that it is the water of 5% (W/W) that described lyophilization powder contains paramount.
4. the described preparation of claim 1 to 3 is characterized in that when forming the injectable mixture of physiology again, and it contains the paclitaxel that concentration is 0.1-3mg/ml.
5. according to the injectable aqueous mixture of the described preparation of claim 1 to 4, it is characterized in that it contains the paclitaxel that concentration is 0.1-3mg/ml.
6. injectable aqueous mixture according to claim 5 is characterized in that it contains the paclitaxel that concentration is 0.5-2.5mg/ml.
7. can be from the injectable mixture of physiology that obtains according to the described anti-tumor agent of aforementioned arbitrary claim.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20020068 | 2002-03-29 | ||
| ITMI2002A000680 | 2002-03-29 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100912563A Division CN1935121A (en) | 2002-03-29 | 2003-03-28 | Improved paclitaxel-based antitumor formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1448132A true CN1448132A (en) | 2003-10-15 |
Family
ID=28687153
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN03108362A Pending CN1448132A (en) | 2002-03-29 | 2003-03-28 | Modified antineoplastic preparation based on Paclitaxel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1448132A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9308180B2 (en) | 2005-08-31 | 2016-04-12 | Abraxis Bioscience, Llc | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
| CN106333941A (en) * | 2016-10-24 | 2017-01-18 | 聊城大学 | Process for preparing paclitaxel albumin compound |
| WO2022184164A1 (en) * | 2021-03-05 | 2022-09-09 | 石药集团中奇制药技术（石家庄）有限公司 | Stable docetaxel albumin nanoparticle composition |
-
2003
- 2003-03-28 CN CN03108362A patent/CN1448132A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9308180B2 (en) | 2005-08-31 | 2016-04-12 | Abraxis Bioscience, Llc | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
| CN106333941A (en) * | 2016-10-24 | 2017-01-18 | 聊城大学 | Process for preparing paclitaxel albumin compound |
| CN106333941B (en) * | 2016-10-24 | 2019-12-13 | 聊城大学 | preparation process of paclitaxel albumin complex |
| WO2022184164A1 (en) * | 2021-03-05 | 2022-09-09 | 石药集团中奇制药技术（石家庄）有限公司 | Stable docetaxel albumin nanoparticle composition |
| CN115025053A (en) * | 2021-03-05 | 2022-09-09 | 石药集团中奇制药技术（石家庄）有限公司 | Stable docetaxel albumin nanoparticle composition |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1935121A (en) | Improved paclitaxel-based antitumor formulation | |
| CN1259902C (en) | Process for producing nanoparticles of paclitaxel and albumin | |
| JP5539839B2 (en) | Compositions and methods for producing microparticles of water-insoluble materials | |
| JP5898627B2 (en) | Therapeutic polymer nanoparticles containing epothilone and methods of making and using the same | |
| EP0577215B1 (en) | Process for obtaining surface modified anticancer nanoparticles | |
| EP0869776B1 (en) | Stabilised nanoparticles capable of being filtered under sterile conditions | |
| CN1151114A (en) | Nanoparticles stab bilized and filterable in sterile conditions | |
| CN1245955C (en) | Thermoprotected microparticle compositions and process for terminal steam sterilization thereof | |
| EP3372226B1 (en) | Targeted hydrophobic anti-tumour drug nanoformulation and preparation method thereof | |
| US9415019B2 (en) | Nanocapsules with a polymer shell | |
| CN101568328B (en) | Microparticles based on an amphiphilic copolymer and on active ingredient(s) with modified release and pharmaceutical formulations containing same | |
| WO2005007136A1 (en) | Methods of making pharmaceutical formulations for the delivery of drugs having low aqueous solubility | |
| KR20090040289A (en) | Pharmaceutical formulations for the sustained release of active ingredient(s), as well as their applications, especially therapeutic | |
| CN1438881A (en) | The Controlled release preparation of insulin and its method | |
| CN1625414A (en) | Pharmaceutical composition | |
| US20040058008A1 (en) | Microparticles having serum as a dispersing agent and process for their preparation and use | |
| CN1973832A (en) | Biodegradable nanometer medicine capsule with CT trace effect and its prepn process | |
| CN1448132A (en) | Modified antineoplastic preparation based on Paclitaxel | |
| JP2007532519A (en) | Use of glycerol dipalmitostearate to improve the bioavailability of protein active ingredients in subcutaneous or intramuscular formulations | |
| CN1475205A (en) | Medicine conveying system--preparation method of solid nano medicine | |
| KR20070003247A (en) | Preparation of core/shell nanoparticles with drug-loaded lipid core using nanoencapsulation | |
| JP2007509989A (en) | Reconfigurable microsphere composition useful as an ultrasound contrast agent | |
| JP5098225B2 (en) | Method for producing fine particles containing hydrophilic active substance | |
| KR101764004B1 (en) | Composition for preventing or treating osteoarthritis, or for relieving joint pain | |
| US11642420B2 (en) | Nanoparticle pharmaceutical delivery system |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |