CN105935350B - A kind of Apremilast sustained-release implant and preparation method thereof - Google Patents
A kind of Apremilast sustained-release implant and preparation method thereof Download PDFInfo
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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Abstract
The present invention provides a kind of Apremilast sustained-release implants, including：Apremilast 30wt%~40wt%；0~20wt% of polylactic acid；Polylactide-polyglycolic acid copolymer 30wt%~60wt%；0~10wt% of Macrogol 6000；Above-mentioned each component total content is 100%.The present invention is using polylactic acid and polylactide-polyglycolic acid copolymer as auxiliary material, Apremilast is prepared into sustained-release implant, by being locally implanted implant, by spreading the degradation release drug with biomaterial, and Drug controlled release speed can be adjusted according to the dosage of excipient substance and ratio, maintain the effective blood drug concentration of target area, reduce the toxic side effect that systemic administration generates, significantly reduce the dosage of administration number of times and administration, the application range of such drug has been widened in the safety for improving medication.
Description
Technical field
The present invention relates to technical field of medicine more particularly to a kind of Apremilast sustained-release implant and its preparation sides
Method.
Background technique
On March 21st, 2014, the Apremilast (Apremilast) that U.S. FDA ratifies Celgene company are used for activity
The treatment of psoriatic arthritis (PsA) adult patients, this is first orally available PsA therapeutic agent of FDA approval listing.
In September, 2014, U.S. FDA ratify again Apremilast for be suitble in light therapy and systemic therapy, severe plaque psoriasis
The treatment of patient.
Currently, it is quick-release tablet that Apremilast, which has listed dosage form, need to take daily twice.It is normal to receive the treatment of Apremilast piece
See that adverse reaction includes diarrhea, nausea, headache, the infection of the upper respiratory tract (incidence>5%).In addition, finding A Pu in clinical research
Patient's depression risk increases after this special piece treatment, and weight loss is obvious, so that Apremilast treatment terminates.It therefore, is reduction
The generation of the adverse reactions such as digestive system caused by Apremilast piece, nervous system increases the compliance of patient medication, exploitation office
The long lasting drug formulations of portion's application are inexorable trends.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing a kind of Apremilast sustained-release implant and its preparation
Method, injection can once work for a long time, and rate of release is controllable.
The present invention provides a kind of Apremilast sustained-release implants, including：
Above-mentioned each component total content is 100%.
Preferably, the polylactic acid content is 5wt%~10wt%.
Preferably, the polylactide-polyglycolic acid copolymer content is 40wt%~60wt%.
Preferably, the Macrogol 6000 content is 5wt%~10wt%.
The present invention also provides a kind of preparation methods of Apremilast sustained-release implant, including：
A) in methylene chloride by Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, Macrogol 6000
Dissolution, obtains solution；
B the obtained solution of step A) is mixed with poly-vinyl alcohol solution), successively passes through high-speed stirred, stirs at low speed, is centrifuged
Particle is collected, it is dry, obtain Apremilast sustained-release implant；
The Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, Macrogol 6000 mass ratio be (30
~40)：(0~20)：(30~60)：(0~10).
Preferably, the step B) in, the obtained solution of step A) is mixed with poly-vinyl alcohol solution it is specially：
The obtained solution of step A) is added drop-wise in poly-vinyl alcohol solution.
Preferably, the revolving speed of the high-speed stirred is 6000~10000 turns/min.
Preferably, the revolving speed stirred at low speed is 50~100 turns/min.
Preferably, the step B) in, the drying is specially：
Freeze-drying, is then dried in vacuo.
The present invention also provides the A Pu that a kind of above-mentioned Apremilast sustained-release implant or above-mentioned preparation method are prepared
This application of special sustained-release implant in the arthritic drug caused by preparation treatment psoriasis or psoriasis.
Compared with prior art, the present invention provides a kind of Apremilast sustained-release implants, including：Apremilast 30wt%
~40wt%；0~20wt% of polylactic acid；Polylactide-polyglycolic acid copolymer 30wt%~60wt%；Macrogol 6000 0
~10wt%；Above-mentioned each component total content is 100%.The present invention is with polylactic acid, polylactide-polyglycolic acid copolymer and poly- second
Glycol 6000 is auxiliary material, and Apremilast is prepared into sustained-release implant, by being locally implanted implant, passes through diffusion and biology
The degradation of material discharges drug, and Drug controlled release speed can be adjusted according to the dosage of excipient substance and ratio, maintains
The effective blood drug concentration of target area reduces the toxic side effect that systemic administration generates, hence it is evident that the dosage of administration number of times and administration is reduced,
The application range of such drug has been widened in the safety for improving medication.
Detailed description of the invention
Fig. 1 is the release profiles of Apremilast sustained-release implant prepared by the embodiment of the present invention 1；
Fig. 2 is the release profiles of Apremilast sustained-release implant prepared by the embodiment of the present invention 2；
Fig. 3 is the release profiles of Apremilast sustained-release implant prepared by the embodiment of the present invention 3；
Fig. 4 is the release profiles of Apremilast sustained-release implant prepared by the embodiment of the present invention 4；
Fig. 5 is the release profiles of Apremilast sustained-release implant prepared by the embodiment of the present invention 5；
Fig. 6 is the release profiles of the Apremilast sustained-release implant of comparative example 1 of the present invention preparation；
Fig. 7 is the release profiles of the Apremilast sustained-release implant of comparative example 2 of the present invention preparation.
Specific embodiment
The present invention provides a kind of Apremilast sustained-release implants, including：
Above-mentioned each component total content is 100%.
Apremilast is prepared into sustained release and planted by the present invention using polylactic acid and polylactide-polyglycolic acid copolymer as auxiliary material
Enter agent, by being locally implanted implant, by spreading the degradation release drug with biomaterial, and can be according to excipient substance
Dosage and ratio adjust Drug controlled release speed, maintain the effective blood drug concentration of target area, reduce systemic administration and generate
Toxic side effect, hence it is evident that reduce administration number of times and administration dosage, improve the safety of medication, widened answering for such drug
Use range.
In the present invention, the content of the Apremilast is 30wt%~40wt%, preferably 33wt%~38wt%, at this
In certain specific embodiments of invention, the content is 30wt%, 35wt% or 40wt%.
The content of the polylactic acid is 0~20wt%, preferably 5wt%~10wt%, in certain specific realities of the invention
It applies in example, the content is 5wt%, 10wt%, 20wt%.
In the present invention, the number-average molecular weight of the polylactic acid is preferably 5000~10000 dalton.
The polylactide-polyglycolic acid copolymer is 30wt%~60wt%, preferably 40wt%~60wt%, at this
In certain specific embodiments of invention, the content is 40wt%, 45wt%, 50wt%, 58wt%, 60wt%.
In the present invention, the number-average molecular weight of the polylactide-polyglycolic acid copolymer is preferably 10000~100000.
The content of the Macrogol 6000 is 0~10wt%, preferably 5wt%~10wt%, of the invention certain
In specific embodiment, the content is 5wt%, 7wt%, 10wt%.
In the present invention, above-mentioned each component total content is 100%.
The present invention is not particularly limited above-mentioned each component source, can be general commercially available.
The present invention also provides the preparation methods of above-mentioned Apremilast sustained-release implant, including：
A) in methylene chloride by Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, Macrogol 6000
Dissolution, obtains solution；
B the obtained solution of step A) is mixed with poly-vinyl alcohol solution), successively passes through high-speed stirred, stirs at low speed, is centrifuged
Particle is collected, it is dry, obtain Apremilast sustained-release implant；
The Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, Macrogol 6000 mass ratio be (30
~40)：(0~20)：(30~60)：(0~10).
First by Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, Macrogol 6000 in methylene chloride
Middle dissolution, obtains dichloromethane solution.
The present invention is to the dosage of methylene chloride and is not particularly limited, and each component is dissolved.
Then above-mentioned solution being mixed with poly-vinyl alcohol solution, the poly-vinyl alcohol solution is polyvinyl alcohol water solution, this
Invention is preferred, after mixing evenly by above-mentioned solution, is added drop-wise in poly-vinyl alcohol solution, the poly-vinyl alcohol solution volume with it is upper
The volume ratio for stating dichloromethane solution is preferably 10~15：1.
The polyvinyl alcohol is emulsifier, and in the polyvinyl alcohol water solution, polyvinyl alcohol content is 2.5~5g/
100mL。
Then high-speed stirred is emulsified, and the revolving speed of the high-speed stirred is preferably 6000~10000 turns/min.The height
The time of speed stirring is preferably 20~30min.
After emulsification sufficiently, then the organic solvent in volatilization dry system is stirred at low speed, the revolving speed stirred at low speed is preferably
50~100 turns/min.The time stirred at low speed is preferably 4~6h.
It is then centrifuged for collecting particle, and dry, Apremilast sustained-release implant can be obtained.
It is currently preferred, after centrifugation, washed with particle of the distilled water to collection.
The present invention is to the method for the drying and is not particularly limited, and can be drying side well known to those skilled in the art
Method, it is currently preferred, first particle is freeze-dried, is then dried in vacuo again.
It is currently preferred, after dry, sterilization treatment is carried out to Apremilast particle.
Above-mentioned Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, the content of Macrogol 6000 with it is above-mentioned
Identical, details are not described herein.
Preparation process provided by the invention is simple, using dissolve, the method for particle processed can be prepared, and carrier material have
There is biodegradable, by injection implantation patient illness part, performance is efficient for a long time to inhibit psoriasis effect.
The present invention also provides the Apremilasts that above-mentioned Apremilast sustained-release implant or above-mentioned preparation method are prepared
Application of the sustained-release implant in the arthritic drug caused by preparation treatment psoriasis or psoriasis.
The present invention provides a kind of novel forms of Apremilast, and in vivo by medicine-releasing system heeling-in, drug is with biological material
The degradation of material and slow release drug, to achieve the purpose that long-term treatment acts on, and improves Apremilast oral tablet institute band
The various disadvantages come.
In order to further illustrate the present invention, below with reference to embodiment to Apremilast sustained-release implant provided by the invention and
Preparation method is described in detail.
Embodiment 1
Raw material：
Apremilast 30wt%；
Polylactide-polyglycolic acid copolymer 60wt%；
Macrogol 6000 10wt%.
Preparation method：
Each component is dissolved in methylene chloride, after mechanical stirring mixes, is added drop-wise in poly-vinyl alcohol solution, 8000 turns/
Min high-speed stirred emulsifies 25min, and then 75 turns/min stirs at low speed 5h, and volatilize dry organic solvent, particle is collected by centrifugation, with steaming
Distilled water washing, is dried in vacuo after freeze-drying, obtains Apremilast particle, and Apremilast sustained release implantation is prepared after sterilizing
Agent.
Release in vitro measurement is carried out to the Apremilast sustained-release implant of preparation, specific method is：
Each measurement sample (n=4, i.e., each prescription carry out the parallel determination of four samples) is placed in 100mL's
The phosphate buffer 50mL containing 0.1% lauryl sodium sulfate, pH7.4 is added in glass tube, and tool is filled in 37 DEG C of water-baths of postposition,
Slight vibration (50rpm).A sample is taken, and carries out content detection within every 10 days, and added new buffer and release in next step
Medicine experiment, when final burst size reaches 90% stopping experiment.
Experimental result is shown in Table 1 and Fig. 1, wherein table 1 is Apremilast sustained release prepared by 1~embodiment of the embodiment of the present application 5
50% and 80% release time of Apremilast implant prepared by implant and 1~comparative example of comparative example 2, Fig. 1 is the application
The release profiles of Apremilast sustained-release implant prepared by embodiment 1.
Apremilast sustained-release implant prepared by 1 1~embodiment of the embodiment of the present application 5 of table and 1~comparative example of comparative example 2
50% and 80% release time
Embodiment 2
Raw material：
The preparation method is the same as that of Example 1.
Release in vitro measurement is carried out to the Apremilast sustained-release implant of preparation according to the method for embodiment 1, the results are shown in Table 1
And Fig. 2, wherein table 1 is Apremilast sustained-release implant and comparative example 1~comparison prepared by 1~embodiment of the embodiment of the present application 5
50% and 80% release time of Apremilast implant prepared by example 2, Fig. 2 are Apremilasts prepared by the embodiment of the present application 2
The release profiles of sustained-release implant.
Embodiment 3
Raw material：
The preparation method is the same as that of Example 1.
Experimental result is shown in Table 1 and Fig. 3, wherein table 1 is Apremilast sustained release prepared by 1~embodiment of the embodiment of the present application 5
50% and 80% release time of Apremilast implant prepared by implant and 1~comparative example of comparative example 2, Fig. 3 is the application
The release profiles of Apremilast sustained-release implant prepared by embodiment 3.
Embodiment 4
Raw material：
The preparation method is the same as that of Example 1.
Experimental result is shown in Table 1 and Fig. 4, wherein table 1 is Apremilast sustained release prepared by 1~embodiment of the embodiment of the present application 5
50% and 80% release time of Apremilast implant prepared by implant and 1~comparative example of comparative example 2, Fig. 4 is the application
The release profiles of Apremilast sustained-release implant prepared by embodiment 4.
Embodiment 5
Raw material：
The preparation method is the same as that of Example 1.
Experimental result is shown in Table 1 and Fig. 5, wherein table 1 is Apremilast sustained release prepared by 1~embodiment of the embodiment of the present application 5
50% and 80% release time of Apremilast implant prepared by implant and 1~comparative example of comparative example 2, Fig. 5 is the application
The release profiles of Apremilast sustained-release implant prepared by embodiment 5.
Through the foregoing embodiment it is found that when main ingredient maintains 30% content, remaining component becomes in the range of the setting
Change the requirement that can preferably meet implant release drug.And there was no significant difference for the rate of release of Examples 1 to 3.
By embodiment 3, embodiment 4 and embodiment 5 by the measurement of release in vitro condition it is found that as Apremilast contains
The rate of release of the raising of amount, this product slightly improves, but simultaneously there was no significant difference for the variation of the measurement result of all releases, says
Bright this product prescription selects amount ranges to have preferable controlled range to the release of prescription.
Comparative example 1
Raw material：
Preparation method：
The lactide-glycolide copolymer (wherein containing lactide 80%, glycolide 20%) and two for being 50000 by molecular weight
Block molecule amount is respectively that 50000 and 2000 poly- propyl ester-polyethylene glycol di-block copolymer is dissolved in methylene chloride, and is added
5 drop Spans 80, stir evenly.It is added after Apremilast, polyethylene glycol at 8000 turns/min, high-speed stirred emulsifies 5min, obtains
To suspension.Above-mentioned suspension is added in 5% aqueous gelatin solution, 8000 turns/min stirs 5min, obtains oil-in-water Bao Gu
Body powder lotion.5h is stirred at room temperature, and solvent flashing is washed with distilled water, and is dried in vacuo after freeze-drying, and Apremilast is obtained
Apremilast sustained-release implant is prepared in particle after sterilizing.
Experimental result is shown in Table 1 and Fig. 6, wherein table 1 is Apremilast sustained release prepared by 1~embodiment of the embodiment of the present application 5
50% and 80% release time of Apremilast implant prepared by implant and 1~comparative example of comparative example 2, Fig. 6 is the application
The release profiles of Apremilast sustained-release implant prepared by comparative example 1.
Comparative example 2
Raw material：
Preparation method is the same as comparative example 1.
Experimental result is shown in Table 1 and Fig. 7, wherein table 1 is Apremilast sustained release prepared by 1~embodiment of the embodiment of the present application 5
50% and 80% release time of Apremilast implant prepared by implant and 1~comparative example of comparative example 2, Fig. 6 is the application
The release profiles of Apremilast sustained-release implant prepared by comparative example 2.
By compared with the release of embodiment and comparative example it is found that the sustained-release implant for preparing of the embodiment in the present invention is more right
Ratio has better slow release effect.
Embodiment 6
Effect experiment
1 experimental material
1.1 experimental drug
(1) test medicine：Apremilast implant.
(2) positive control medicine：Apremilast tablet.
(3) auxiliary material reference material：Polylactic acid (PLA), polylactide-polyglycolic acid copolymer (PLGA) and polyethylene glycol
6000, it is prepared into particle implant.
1.2 experimental animal：SCID nude mouse, 18~20g, male, 4 week old.
1.3 diseased mice sources：Xenograft model.
2, experimental method
2.1, by manual method, acquire the dermatoplasty of psoriatic's active stage in SCID mice back epidermis, filter out
The mouse for meeting requirement of experiment is gone forward side by side row stochastic grouping administration.Medication is to plant the Apremilast of above embodiments preparation
Enter intramuscular at agent or auxiliary material control implant injection mouse transplanting.Positive control Apremilast tablet gastric infusion.
2.2 groupings and administration
(1) animal packet and dosage are arranged
Mouse is randomly divided into auxiliary material control group, positive controls, test medicine group.Test medicine group successively uses relatively
The implant of five embodiments answered and the preparation of two comparative examples, number of animals are every group 6.Auxiliary material control animals number is 12
Only.Positive controls, which are fed, gives Apremilast 5mg/kg, BID, and number of animals is 6.
(2) it is administered
GP TH at modeling 10 days.
It is used in test medicine group according to each comparative example in embodiment and comparative example 1~2 each in Examples 1 to 5
6 experiment mices being grouped at random inject drug delivery implant.
Positive controls (n=6) give Apremilast tablet using stomach-filling.
Auxiliary material control group (n=12) injects blank implant.
2.3 observation index
The general status of animal is observed during test, food-intake is periodically weighed, and routine observation mouse skin changes feelings
Condition.
2.4 evaluation criterions and time：
The treatment rate of each treatment group is measured after being administered 4 weeks, measuring method is as follows：
Treatment rate=(auxiliary material control group be averaged diseased epidermis area-treatment group's group be averaged diseased epidermis area)/auxiliary material pair
According to organizing average diseased epidermis area × 100%,.
3 test results
According to above embodiments 1~5 and comparative example 1~2 all to treatment group in certain Apremilast amount ranges
Mouse skin psoriasis, which has, significantly treats or inhibits effect, although various dose effectively can inhibit mouse skin to fall ill,
But the treatment rate of release different with Apremilast implant, mouse skin serviceability rate have certain otherness.Embodiment 1
~5 and comparative example 1~2 treatment group mouse epidermis illness area compared to start to occur lesion area reduce 40.34%,
45.89%, 50.99%, 59.87%, 60.94% and 34.05%, 38.41%；Compared with model group, Examples 1 to 5 and right
1~2 group of epidermis illness inhibiting rate of ratio has certain otherness.Each group mouse skin treatment rate relatively see the table below 2.
The comparison of 2 each group mouse weight of table, dermal treatment rate etc.
4, interpretation of result
This experimental result shows Apremilast implant to the severe combined immunodeficiency (SCID) using transplanting application on human skin
Good therapeutic effect is shown in mouse model, and there is more preferably therapeutic effect to Apremilast oral tablet, is tried simultaneously
Yan Ge group is showed no overt toxicity reaction.
As can be seen from the above embodiments, Apremilast sustained-release implant prepared by the present invention has excellent slow release effect.Point
Not compared with comparative example, the embodiment of Apremilast sustained-release implant has better therapeutic effect compared with comparative example.
Apremilast sustained-release implant prepared by the present invention compared with Apremilast oral tablet, have the effect of it is similar,
But few with the administration number of times and final therapeutic effect of sustained-release implant of the invention is more excellent, it is complete using general technical method
At Apremilast implant cannot reach same therapeutic effect.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (9)
1. a kind of Apremilast sustained-release implant, including：
Above-mentioned each component total content is 100%.
2. Apremilast sustained-release implant according to claim 1, which is characterized in that the polylactic acid content is 5wt%
~10wt%.
3. Apremilast sustained-release implant according to claim 1, which is characterized in that the polyglycolic-polylactic acid
Copolymer level is 40wt%~60wt%.
4. a kind of preparation method of Apremilast sustained-release implant, including：
A) Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, Macrogol 6000 are dissolved in methylene chloride,
Obtain solution；
B the obtained solution of step A) is mixed with poly-vinyl alcohol solution), successively passes through high-speed stirred, stirs at low speed, be collected by centrifugation
Particle, it is dry, obtain Apremilast sustained-release implant；
The Apremilast, polylactic acid, polylactide-polyglycolic acid copolymer, Macrogol 6000 mass ratio be (30~
40)：(0~20)：(30~60)：(0~10).
5. the preparation method according to claim 4, which is characterized in that the step B) in, it will
Step A) obtained solution mixes with poly-vinyl alcohol solution and is specially：
The obtained solution of step A) is added drop-wise in poly-vinyl alcohol solution.
6. the preparation method according to claim 4, which is characterized in that the revolving speed of the high-speed stirred is 6000~10000
Turn/min.
7. the preparation method according to claim 4, which is characterized in that the revolving speed stirred at low speed be 50~100 turns/
min。
8. according to preparation method as claimed in claim 4, which is characterized in that the step B) in, the drying is specially：
Freeze-drying, is then dried in vacuo.
9. the described in any item Apremilast sustained-release implants of claims 1 to 3 or the described in any item systems of claim 4~8
The Apremilast sustained-release implant that Preparation Method is prepared arthritic drug caused by preparation treatment psoriasis or psoriasis
In application.
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