CN104922062B - A kind of Bexarotene nano suspension - Google Patents
A kind of Bexarotene nano suspension Download PDFInfo
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- CN104922062B CN104922062B CN201510278662.XA CN201510278662A CN104922062B CN 104922062 B CN104922062 B CN 104922062B CN 201510278662 A CN201510278662 A CN 201510278662A CN 104922062 B CN104922062 B CN 104922062B
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Abstract
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of Bexarotene nano suspension.It is characterized in that Bexarotene nano suspension is made by Bexarotene and surfactant.Using polyvinylpyrrolidone as surfactant.And the weight ratio of Bexarotene and surfactant is preferably 1:1‑1:4.The present invention can increase medicament contg, and stable quality is good, and toxic side effect is low, and average grain diameter is about 100~400nm.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more particularly to a kind of Bexarotene nano suspension.
Background technology
Vitamin A acid (Retinoic acid, RA) class compound is for treating multiple dermatosis, such as photoaged skin, angle
Change dermatoses etc.；But it in all therapeutic effects of retinoid compounds, most study is for preventing and controlling
Some malignant tumours are treated, including breast cancer, lung cancer, cervical carcinoma, cutaneum carcinoma etc., it can adjust many tumor cell differentiations, suppression
Growth of tumour cell processed and induction tumour cell programmed death.
Bexarotene (Bexarotene) is first and is approved by the FDA in the United States for treating skin T (shown in structural formula as I)
The Tretinoin X receptor class drugs of cell lymphoma (CTCL), bioactivity is higher, and side effect is relatively fewer.Nearest research is found
Bexarotene shows very high bioactivity in terms of the malignant tumours such as treatment lung cancer, breast cancer.At present, U.S. Ligand systems
The effect of medicine company is being tested, and verification Bexarotene and classic chemotherapy medicine are in non-small cell lung cancer and verification bud Sa
Preventive and therapeutic actions of the Luo Ding in lung cancer.Bexarotene is as biologically active agents and chemotherapy drugs in combination application simultaneously
With good prospect.
The good antitumor activity of Bexarotene tool, but its solubility very little in water, lead to its bioavilability
It is low.According to the literature, Bexarotene is dissolved in the organic solvents such as methanol, ethyl alcohol and dimethyl sulfoxide (DMSO).It lists at present
Bexarotene dosage form has capsule and gelling agent, since the extremely low water solubility of Bexarotene is difficult that parenteral solution is made.Ordinary preparation
Dissolution rate is poor, and bioavilability is low, also bigger with intraindividual difference between individual.Bexarotene has non-in anti-tumor aspect
Often high application value, so clinically needing a kind of safe, stability is good, bioavilability height and patient is facilitated to use
Preparation.
Nano suspension is under the action of stabilizer, by drug particle dispersion in water, forms stable nanometer jelly
Dispersion.The pure drug granule of Nano Particle is stablized by the charge effect or/and stereoeffect of surfactant in system
Suspension in the solution, wherein the average grain diameter of drug is generally between 100-1000nm.Nano suspension can realize more ways
Diameter is administered, including being administered orally, being injected intravenously administration, ophthalmic administration, inhalation etc..Nano suspension can significantly increase
Solubility, dissolution rate and the bioavilability of insoluble drug, and in preparation content of dispersion can reduce greatly dosage and time
Number reduces adverse reaction, improves drug safety.
In conclusion Bexarotene is made nano suspension, small to reach toxic side effect, stability is good, increases medicine
The purpose of object bioavilability.Have not yet to see the report about Bexarotene nano suspension and preparation method thereof.
Invention content
The object of the present invention is to provide one kind can increase medicament contg, improves drug bioavailability, reduces to medicine toxicity
Bexarotene nano suspension, to realize clinical practice.
It is a further object to provide the preparation methods of above-mentioned Bexarotene nano suspension.
The technical solution adopted by the present invention is：A kind of Bexarotene nano suspension, by Bexarotene and surfactant
It is made.
In the preparation of Bexarotene nano suspension, dosage of surfactant can excessively make nano suspension stability instead
Decline, but surfactant uses very few, easily reunites between particle.Through many experiments, above-mentioned Bexarotene is received
The weight ratio of rice suspension, Bexarotene and surfactant is 1:1~1:7, preferred weight ratio 1:1~1:4.
Above-mentioned Bexarotene nano suspension, the surfactant be selected from soybean lecithin, PLURONICS F87,
Polyvinylpyrrolidone, polyoxyethylene non-ionic surfactant or the one or two or more kinds of of lauryl sodium sulfate mix
It closes.Preferred surfactant is polyvinylpyrrolidone.
A kind of preparation method of Bexarotene nano suspension, includes the following steps：
1) Bexarotene and surfactant are taken by above-mentioned proportioning；
2) Bexarotene is dissolved in 0.1mol/L sodium hydroxide solutions, be then slowly dropped to containing surfactant
In 0.1mol/L hydrochloric acid solutions, magnetic agitation obtains the suspension of emulsus；
3) above-mentioned suspension is centrifuged, taking precipitate, and adds in isometric distilled water and disperseed；
4) solution after dispersion in ultrasonic cell disruptor is crushed, 10- is handled under conditions of 180W
20min is to get Bexarotene nanosuspension.
The beneficial effects of the invention are as follows：The present invention overcomes Bexarotene indissoluble sex chromosome mosaicisms, improve its bioavilability,
Increase curative effect, widen its clinical practice.The present invention uses acid-base neutralization method to handle sample, in hydrochloric acid and sodium hydroxide
With generation sodium chloride salt, this does not use organic solvent in the process so that toxicity reduces, and the surface that the present invention uses
Activating agent is pharmaceutic adjuvant, safe, nonirritant, physiological-toxicity-free, has good biocompatibility.The present invention is made
Preparation method ultrasonic cell disruptor preparation process is simple, convenient.Bexarotene nano suspension prepared by the present invention,
Particle is spherical in shape, and particle size is uniform, and grain size is less than 500nm.Bexarotene nano suspension prepared by the present invention, Bexarotene
Rate of dissolution increase and release in vitro it is uniform, therefore change the distribution of drug in vivo, reduce toxic side effect.
Description of the drawings
Fig. 1 is the grain size distribution of Bexarotene nano suspension prepared by embodiment 1.
Fig. 2 is Bexarotene nano suspension In-vitro release curves prepared by embodiment 1.
Wherein, a- bulk pharmaceutical chemicals Bexarotene；B- physical mixtures；The Bexarotene nano suspension of c- embodiments 1.
Fig. 3 is Bexarotene nano suspension prepared by Bexarotene and embodiment 1, concentration curve during medicine；
Wherein, a- bulk pharmaceutical chemicals Bexarotene；The Bexarotene nano suspension of c- embodiments 1.
Specific embodiment
1 Bexarotene nano suspension of embodiment
Composition is：Bexarotene 0.015g is as main ingredient, and 0.015g polyvinylpyrrolidones are as surfactant.
Specific preparation method is as follows：
Bexarotene 0.015g is weighed, in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to
In the 0.1mol/L hydrochloric acid solutions of the 10ml of polyvinylpyrrolidone containing 0.015g, magnetic agitation obtains the suspension of emulsus
Liquid.The suspension centrifugation for the emulsus that magnetic agitation is obtained, takes its sediment, and the distilled water for adding in 20ml is disperseed.It will
Solution after dispersion, in power to crush 10min under conditions of 180W, obtains bud under ultrasonic cell disruptor pulverization
Salol fourth nano suspension.
2 Bexarotene nano suspension of embodiment
Composition is：0.015g Bexarotenes are as main ingredient, and 0.0225g polyvinylpyrrolidones are as surface-active
Agent.
Specific preparation method is as follows：
Bexarotene 0.015g is weighed, in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to
In the 0.1mol/L hydrochloric acid solutions of the 10ml of polyvinylpyrrolidone containing 0.0225g, magnetic agitation obtains the suspension of emulsus
Liquid.The suspension centrifugation for the emulsus that magnetic agitation is obtained, takes its sediment, and the distilled water for adding in 20ml is disperseed.It will
Solution after dispersion, in power to crush 10min under conditions of 180W, obtains bud under ultrasonic cell disruptor pulverization
Salol fourth nano suspension.
3 Bexarotene nano suspension of embodiment
Composition is：Bexarotene 0.015g is as main ingredient, and 0.03g polyvinylpyrrolidones are as surfactant.
Specific preparation method is as follows：
Bexarotene 0.015g is weighed, in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to
In the 0.1mol/L hydrochloric acid solutions of the 10ml of polyvinylpyrrolidone containing 0.03g, magnetic agitation obtains the suspension of emulsus.
The suspension centrifugation for the emulsus that magnetic agitation is obtained, takes its sediment, and the distilled water for adding in 20ml is disperseed.It will dispersion
Solution afterwards, in power to crush 10min under conditions of 180W, obtains bud salol under ultrasonic cell disruptor pulverization
Fourth nano suspension.
4 Bexarotene nano suspension of embodiment
Composition is：Bexarotene 0.015g is as main ingredient, and 0.0375g polyvinylpyrrolidones are as surface-active
Agent.
Specific preparation method is as follows：
Bexarotene 0.015g is weighed, in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to
In the 0.1mol/L hydrochloric acid solutions of the 10ml of polyvinylpyrrolidone containing 0.0375g, magnetic agitation obtains the suspension of emulsus
Liquid.The suspension centrifugation for the emulsus that magnetic agitation is obtained, takes its sediment, and the distilled water for adding in 20ml is disperseed.It will
Solution after dispersion, in power to crush 10min under conditions of 180W, obtains bud under ultrasonic cell disruptor pulverization
Salol fourth nano suspension.
5 Bexarotene nano suspension of embodiment
Composition is：Bexarotene 0.015g is as main ingredient, and 0.045g polyvinylpyrrolidones are as surfactant.
Specific preparation method is as follows：
Bexarotene 0.015g is weighed, in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to
In the 0.1mol/L hydrochloric acid solutions of the 10ml of polyvinylpyrrolidone containing 0.045g, magnetic agitation obtains the suspension of emulsus
Liquid.The suspension centrifugation for the emulsus that magnetic agitation is obtained, takes its sediment, and the distilled water for adding in 20ml is disperseed.It will
Solution after dispersion, in power to crush 10min under conditions of 180W, obtains bud under ultrasonic cell disruptor pulverization
Salol fourth nano suspension.
6 Bexarotene nano suspension of embodiment
Composition is：Bexarotene 0.015g is as main ingredient, and 0.0525g polyvinylpyrrolidones are as surface-active
Agent.
Specific preparation method is as follows：
Bexarotene 0.015g is weighed, in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to
In the 0.1mol/L hydrochloric acid solutions of the 10ml of polyvinylpyrrolidone containing 0.0525g, magnetic agitation obtains the suspension of emulsus
Liquid.The suspension centrifugation for the emulsus that magnetic agitation is obtained, takes its sediment, and the distilled water for adding in 20ml is disperseed.It will
Solution after dispersion, in power to crush 10min under conditions of 180W, obtains bud under ultrasonic cell disruptor pulverization
Salol fourth nano suspension.
7 Bexarotene nano suspension of embodiment
Composition is：Bexarotene 0.015g is as main ingredient, and 0.06g polyvinylpyrrolidones are as surfactant.
Specific preparation method is as follows：
Bexarotene 0.015g is weighed, in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to
In the 0.1mol/L hydrochloric acid solutions of the 10ml of polyvinylpyrrolidone containing 0.06g, magnetic agitation obtains the suspension of emulsus.
The suspension centrifugation for the emulsus that magnetic agitation is obtained, takes its sediment, and the distilled water for adding in 20ml is disperseed.It will dispersion
Solution afterwards, in power to crush 10min under conditions of 180W, obtains bud salol under ultrasonic cell disruptor pulverization
Fourth nano suspension.
8 performance test of embodiment
(1) the Bexarotene nano suspension for preparing embodiment 1-7 carries out transmission electron microscope observing, it is seen then that the bud of preparation
Salol fourth nano suspension particle is spherical in shape, and medical surfaces package layer of surface activating agent, grain size is less than 500nm.By bud Sa
The transmission electron microscope picture of Luo Ding nano suspensions is as it can be seen that Bexarotene nano suspension has well-regulated spherical structure, and outer bread
It is wrapped with layer of surface activating agent.
Fig. 1 is the grain size distribution of Bexarotene nano suspension prepared by embodiment 1, it can be seen from figure 1 that 1 institute of embodiment
The average grain diameter of the Bexarotene nano suspension of preparation is 230nm.
Comprehensive Bexarotene transmission electron microscope picture and Fig. 1 are it is found that the nano suspension prepared by embodiment 1 not only has rule
Spherical structure, and average grain diameter is 230nm, but the average grain diameter prepared by other embodiment is 260nm or so, according to reality
The nano suspension average grain diameter applied prepared by example 1 is small, and small particles specific surface area is larger, has higher surface can so as to receive
Rice suspension particle is more stablized.
(2) the Bexarotene nano suspension for preparing embodiment 1-7 carries out extracorporeal releasing experiment, it is seen then that Bexarotene
The had good sustained release effect of nano suspension, and without phenomenon of burst release.
Fig. 2 is the nano suspension In-vitro release curves prepared by embodiment 1, wherein, a- bulk pharmaceutical chemicals Bexarotenes；B- objects
Manage mixture (the direct mixing of bulk pharmaceutical chemicals Bexarotene and surfactant)；The Bexarotene nano suspension of c- embodiments 1.
Bexarotene nano suspension prepared by embodiment 1 when in 20min, dissolution rate is 70%, 120min dissolution rate reach
100%, and dissolution rate is 21% when dissolution rate of the physical mixture in 20min is 14%, 120min, bulk pharmaceutical chemicals exist
Dissolution rate when dissolution rate during 20min is only 5%, 120min is only 12%.Illustrate the bud salol prepared by embodiment 1
Fourth nano suspension can significantly improve drug dissolution.The sustained release effect of Bexarotene nano suspension prepared by embodiment 1
Fruit is more preferable, and without phenomenon of burst release, so as to extend the action time of drug.
(3) the Bexarotene nano suspension for preparing embodiment 1-7 carries out concentration curve during medicine, it is seen then that Bexarotene
Nano suspension shows the blood concentration of bigger.
Concentration curve when Fig. 3 is the nano suspension medicine prepared by embodiment 1, wherein, a- bulk pharmaceutical chemicals Bexarotenes；C- is real
Apply the Bexarotene nano suspension of example 1.From the figure 3, it may be seen that the blood medicine of the Bexarotene nano suspension prepared by embodiment 1 is dense
Degree is significantly higher than Bexarotene active compound.In 240min, the blood concentration of the Bexarotene nano suspension prepared by embodiment 1
For 500ng/ml, and the blood concentration of Bexarotene bulk pharmaceutical chemicals is 300ng/ml.It can be seen that in same point, with Bexarotene
Bulk pharmaceutical chemicals are compared, and Bexarotene nano suspension shows the blood concentration of bigger.And the AUC of Bexarotene nano suspension
Thus bigger demonstrates the oral administration biaavailability that Bexarotene nano suspension improves bulk pharmaceutical chemicals.
(4) Zeta potential test is carried out to the Bexarotene nano suspension prepared by embodiment 1, absolute value is
24mv, the bigger Charge repulsion proved between particle of value is larger to be not susceptible to assemble, so that nano suspension can
Exist with more stable state.
(5) PDI assessment of indices, value 0.1, explanation are carried out to the Bexarotene nano suspension prepared by embodiment 1
It is most stable.
(6) differential scanning is carried out to the Bexarotene nano suspension prepared by embodiment 1 and Bexarotene bulk pharmaceutical chemicals
Thermometric analysis, as a result, it has been found that, Bexarotene bulk pharmaceutical chemicals at 220.4 DEG C there are a melting peak, and Bexarotene nanometer suspension
Agent is also that about at 210.1 DEG C or so, there are one melting peaks.The Bexarotene bulk pharmaceutical chemicals of gained and Bexarotene nano suspension
Differential heating scan collection of illustrative plates feature peak position it is almost the same, illustrate drug be made into nano suspension after crystal form do not become
Change.
(7) the Bexarotene nano suspension for preparing embodiment 1-5, is placed at room temperature for, and is taken when 0,1,2,3 week
Sample is surveyed by transmission electron microscope observation nano suspension form, while using 2000 nano-particle size analysis instrument of Malvern
Grain size, polydispersity coefficient and Zeta potential are measured, investigates the stability of system.It the results are shown in Table 1.
Table 1
By table 1 as it can be seen that sample room temperature 3 weeks, for grain size without significant change, whole system keeps good in a long time
Stability.
Claims (1)
1. a kind of preparation method of Bexarotene nano suspension, it is characterised in that preparation method includes the following steps：Weigh bud
Salol fourth 0.015g in the sodium hydroxide solution for the 0.1mol/L for being dissolved in 10ml, is then slowly dropped to poly- containing 0.015g
In the 0.1mol/L hydrochloric acid solutions of the 10ml of vinylpyrrolidone, magnetic agitation obtains the suspension of emulsus；Magnetic agitation is obtained
The suspension centrifugation of the emulsus arrived, takes its sediment, and the distilled water for adding in 20ml is disperseed, by the solution after dispersion super
Under sound wave cell disruptor pulverization, in power to crush 10min under conditions of 180W, Bexarotene nanometer suspension is obtained
Agent.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1806798A (en) * | 2006-02-23 | 2006-07-26 | 北京阜康仁生物制药科技有限公司 | Medicinal composition making bexarotene as active ingredients, its preparation method and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1806798A (en) * | 2006-02-23 | 2006-07-26 | 北京阜康仁生物制药科技有限公司 | Medicinal composition making bexarotene as active ingredients, its preparation method and use |
Non-Patent Citations (1)
| Title |
|---|
| Bexarotene nanocrystal—Oral and parenteral formulation development;Lijiang Chen etal;《European Journal of Pharmaceutics and Biopharmaceutics》;20131212;参见160页摘要、161页右栏第5段、161页右栏第7-8段、163页左栏第7-8段和163右栏表1 * |
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