CN105935350A - Apremilast sustained-release implant and preparation method thereof - Google Patents
Apremilast sustained-release implant and preparation method thereof Download PDFInfo
- Publication number
- CN105935350A CN105935350A CN201510957710.8A CN201510957710A CN105935350A CN 105935350 A CN105935350 A CN 105935350A CN 201510957710 A CN201510957710 A CN 201510957710A CN 105935350 A CN105935350 A CN 105935350A
- Authority
- CN
- China
- Prior art keywords
- apremilast
- preparation
- implant
- release
- sustained
- 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.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The invention provides an Apremilast sustained-release implant, which includes 30wt%-40wt% of Apremilast, 0-20wt% of polylactic acid, 30wt%-60wt% of polylactic acid-polyglycolic acid copolymer and 0-10wt% of polyethylene glycol 60000, wherein the total content of the above components is 100%. The method uses polylactic acid and polylactic acid-polyglycolic acid copolymer as auxiliary materials to prepare Apremilast into the sustained-release implant; by local injection of the implant, diffusion and degradation of biological materials, the drug is released; and the drug release speed can be adjusted and controlled according to the amount and ratio of drug excipients. The implant maintains the effective blood concentration of a target site, reduces toxic and side effects produced by systemic medication, significantly reduces the number of medication and drug dose, improves medication safety, and broadens the application scope of such drugs.
Description
Technical field
The present invention relates to technical field of medicine, particularly relate to a kind of Apremilast sustained-release implant and preparation side thereof
Method.
Background technology
On March 21st, 2014, U.S. FDA ratifies the Apremilast (Apremilast) of Celgene company for activeness
The treatment of psoriatic arthritis (PsA) adult patients, this is first orally available PsA medicine of FDA approval listing.
In JIUYUE, 2014, U.S. FDA ratify again Apremilast for being suitable in phototherapy and whole body therapeutic, severe plaque psoriasis
The treatment of patient.
At present, it is quick-release tablet that Apremilast has listed dosage form, need to take twice every day.Often accept the treatment of Apremilast sheet
See untoward reaction include diarrhoea, feel sick, headache, upper respiratory tract infection (incidence rate > 5%).Additionally, clinical research finds A Pu
After this special sheet treatment, patient's depression risk increases, and loses weight substantially so that Apremilast treatment terminates.Therefore, for reducing
The generation of the untoward reaction such as digestive system that Apremilast sheet causes, nervous system, increases the compliance of patient medication, exploitation office
The long lasting drug formulations of portion's application is inexorable trend.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of Apremilast sustained-release implant and preparation thereof
Method, injection once can onset for a long time, rate of release is controlled.
The invention provides a kind of Apremilast sustained-release implant, including:
Above-mentioned each component total content is 100%.
Preferably, described polylactic acid content is 5wt%～10wt%.
Preferably, described PLGA content is 40wt%～60wt%.
Preferably, described polyethylene glycol 6000 content is 5wt%～10wt%.
Present invention also offers the preparation method of a kind of Apremilast sustained-release implant, including:
A) by Apremilast, polylactic acid, PLGA, polyethylene glycol 6000 in dichloromethane
Dissolve, obtain solution；
B) by step A) solution that obtains mixes with poly-vinyl alcohol solution, sequentially passes through high-speed stirred, stirring at low speed, centrifugal
Collect microgranule, be dried, obtain Apremilast sustained-release implant；
Described Apremilast, polylactic acid, PLGA, the mass ratio of polyethylene glycol 6000 are (30
～40): (0～20): (30～60): (0～10).
Preferably, described step B) in, by step A) solution that obtains mix with poly-vinyl alcohol solution particularly as follows:
By step A) solution that obtains is added drop-wise in poly-vinyl alcohol solution.
Preferably, the rotating speed of described high-speed stirred is 6000～10000 turns/min.
Preferably, the rotating speed of described stirring at low speed is 50～100 turns/min.
Preferably, described step B) in, described be dried particularly as follows:
Lyophilization, is then vacuum dried.
Present invention also offers a kind of above-mentioned Apremilast sustained-release implant, or the A Pu that above-mentioned preparation method prepares
This special sustained-release implant application in the arthritic medicine that preparation treatment psoriasis or psoriasis cause.
Compared with prior art, the invention provides a kind of Apremilast sustained-release implant, including: Apremilast 30wt%
～40wt%；Polylactic acid 0～20wt%；PLGA 30wt%～60wt%；Polyethylene glycol 6000 0
～10wt%；Above-mentioned each component total content is 100%.The present invention is with polylactic acid, PLGA and poly-second
Glycol 6000 is adjuvant, and Apremilast is prepared as sustained-release implant, by being locally implanted implant, by diffusion and biology
The degraded release medicine of material, and Drug controlled release speed can be regulated according to the consumption of excipient substance and ratio, maintain
The effective blood drug concentration of target site, reduces the toxic and side effects that systemic administration produces, hence it is evident that reduce administration number of times and the dosage of administration,
Improve the safety of medication, widen the range of application of this type of medicine.
Accompanying drawing explanation
Fig. 1 is the release profiles of the Apremilast sustained-release implant of the embodiment of the present invention 1 preparation；
Fig. 2 is the release profiles of the Apremilast sustained-release implant of the embodiment of the present invention 2 preparation；
Fig. 3 is the release profiles of the Apremilast sustained-release implant of the embodiment of the present invention 3 preparation；
Fig. 4 is the release profiles of the Apremilast sustained-release implant of the embodiment of the present invention 4 preparation；
Fig. 5 is the release profiles of the Apremilast sustained-release implant of the embodiment of the present invention 5 preparation；
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.
Detailed description of the invention
The invention provides a kind of Apremilast sustained-release implant, including:
Above-mentioned each component total content is 100%.
Apremilast, with polylactic acid and PLGA as adjuvant, is prepared as slow release and plants by the present invention
Enter agent, by being locally implanted implant, by the degraded release medicine of diffusion and biomaterial, and can be according to excipient substance
Consumption and ratio regulate Drug controlled release speed, maintain the effective blood drug concentration of target site, reduce systemic administration and produce
Toxic and side effects, hence it is evident that reducing administration number of times and the dosage of administration, improve the safety of medication, that has widened this type of medicine should
Use scope.
In the present invention, the content of described Apremilast is 30wt%～40wt%, preferably 33wt%～38wt%, at this
In some specific embodiment of invention, described content is 30wt%, 35wt% or 40wt%.
The content of described polylactic acid is 0～20wt%, preferably 5wt%～10wt%, specifically real in some of the present invention
Executing in example, described content is 5wt%, 10wt%, 20wt%.
In the present invention, the number-average molecular weight of described polylactic acid is preferably 5000～10000 dalton.
Described PLGA is 30wt%～60wt%, preferably 40wt%～60wt%, at this
In some specific embodiment of invention, described content is 40wt%, 45wt%, 50wt%, 58wt%, 60wt%.
In the present invention, the number-average molecular weight of described PLGA is preferably 10000～100000.
The content of described polyethylene glycol 6000 is 0～10wt%, preferably 5wt%～10wt%, in some of the present invention
In specific embodiment, described content is 5wt%, 7wt%, 10wt%.
In the present invention, above-mentioned each component total content is 100%.
The present invention all without particular determination, can be the most commercially available to above-mentioned each Component Source.
Present invention also offers the preparation method of above-mentioned Apremilast sustained-release implant, including:
A) by Apremilast, polylactic acid, PLGA, polyethylene glycol 6000 in dichloromethane
Dissolve, obtain solution；
B) by step A) solution that obtains mixes with poly-vinyl alcohol solution, sequentially passes through high-speed stirred, stirring at low speed, centrifugal
Collect microgranule, be dried, obtain Apremilast sustained-release implant；
Described Apremilast, polylactic acid, PLGA, the mass ratio of polyethylene glycol 6000 are (30
～40): (0～20): (30～60): (0～10).
First by Apremilast, polylactic acid, PLGA, polyethylene glycol 6000 at dichloromethane
Middle dissolving, obtains dichloromethane solution.
The present invention there is no particular determination to the consumption of dichloromethane, each component is dissolved.
Then being mixed with poly-vinyl alcohol solution by above-mentioned solution, described poly-vinyl alcohol solution is polyvinyl alcohol water solution, this
Invention preferably, after uniform for above-mentioned solution stirring, is added drop-wise in poly-vinyl alcohol solution, and described poly-vinyl alcohol solution volume is with upper
The volume ratio stating dichloromethane solution is preferably 10～15:1.
Described polyvinyl alcohol is emulsifying agent, and in described polyvinyl alcohol water solution, polyvinyl alcohol content is 2.5～5g/
100mL。
Then high-speed stirred carries out emulsifying, and the rotating speed of described high-speed stirred is preferably 6000～10000 turns/min.Described height
The time of speed stirring is preferably 20～30min.
After emulsifying fully, then the organic solvent in stirring at low speed volatilization dry system, the rotating speed of described stirring at low speed is preferably
50～100 turns/min.The time of described stirring at low speed is preferably 4～6h.
It is then centrifuged for collecting microgranule, and is dried, i.e. can get Apremilast sustained-release implant.
Currently preferred, after being centrifuged, with distilled water, the microgranule collected is washed.
The present invention there is no particular determination to described dry method, the dry side that can be well known to those skilled in the art
Method, currently preferred, first microgranule is carried out lyophilization, be vacuum dried the most again.
Currently preferred, after drying, Apremilast microgranule is carried out sterilization treatment.
Above-mentioned Apremilast, polylactic acid, PLGA, polyethylene glycol 6000 content with above-mentioned
Identical, do not repeat them here.
The preparation technology that the present invention provides is simple, uses dissolving, the method for microgranule processed to prepare, and carrier material tool
There is biodegradable, implant patient illness part by injection, play long-term efficient suppression psoriasis effect.
Present invention also offers above-mentioned Apremilast sustained-release implant, or the Apremilast that above-mentioned preparation method prepares
Sustained-release implant application in the arthritic medicine that preparation treatment psoriasis or psoriasis cause.
The invention provides the novel form of a kind of Apremilast, by medicine-releasing system heeling-in in vivo, medicine is along with biological material
The degraded of material and slow Slow release, thus reach the purpose of long-term treatment effect, improve Apremilast oral tablet and carried
The various disadvantages come.
In order to further illustrate the present invention, the Apremilast sustained-release implant that the present invention provided below in conjunction with embodiment and
Its preparation method is described in detail.
Embodiment 1
Raw material:
Apremilast 30wt%；
PLGA 60wt%；
Polyethylene glycol 6000 10wt%.
Preparation method:
Each component is dissolved in dichloromethane, after mechanical agitation mixing, is added drop-wise in poly-vinyl alcohol solution, 8000 turns/
Min high-speed stirred emulsifying 25min, then 75 turns/min stirring at low speed 5h, volatilize dry organic solvent, and centrifugal collection microgranule, with steaming
Distilled water is washed, and lyophilization final vacuum is dried, and obtains Apremilast microgranule, prepares Apremilast slow release and implant after sterilizing
Agent.
The Apremilast sustained-release implant of preparation is carried out release in vitro mensuration, method particularly includes:
Each mensuration sample (n=4, the most each prescription carries out the parallel assay of four samples) is positioned over 100mL's
Glass tubing, adds containing 0.1% sodium lauryl sulphate, the phosphate buffer 50mL of pH7.4, and tool is filled in rearmounted 37 DEG C of water-baths,
Slight vibration (50rpm).Within every 10 days, take a sample, and carry out content detection, and add new buffer and carry out next step and release
Medicine is tested, when final burst size reaches 90% stopping experiment.
Experimental result is shown in Table 1 and Fig. 1, and wherein, table 1 is the embodiment of the present application 1～the Apremilast slow release of embodiment 5 preparation
50% and 80% release time of the Apremilast implant of implant and comparative example 1～comparative example 2 preparation, Fig. 1 is the application
The release profiles of the Apremilast sustained-release implant of embodiment 1 preparation.
Table 1 the embodiment of the present application 1～embodiment 5 and comparative example 1～the Apremilast sustained-release implant of comparative example 2 preparation
50% and 80% release time
Embodiment 2
Raw material:
Preparation method is with embodiment 1.
According to the method for embodiment 1, the Apremilast sustained-release implant of preparation is carried out release in vitro mensuration, the results are shown in Table 1
And Fig. 2, wherein, table 1 is the embodiment of the present application 1～the Apremilast sustained-release implant of embodiment 5 preparation and comparative example 1～contrasts
50% and 80% release time of the Apremilast implant of example 2 preparation, Fig. 2 is the Apremilast of the embodiment of the present application 2 preparation
The release profiles of sustained-release implant.
Embodiment 3
Raw material:
Preparation method is with embodiment 1.
Experimental result is shown in Table 1 and Fig. 3, and wherein, table 1 is the embodiment of the present application 1～the Apremilast slow release of embodiment 5 preparation
50% and 80% release time of the Apremilast implant of implant and comparative example 1～comparative example 2 preparation, Fig. 3 is the application
The release profiles of the Apremilast sustained-release implant of embodiment 3 preparation.
Embodiment 4
Raw material:
Preparation method is with embodiment 1.
Experimental result is shown in Table 1 and Fig. 4, and wherein, table 1 is the embodiment of the present application 1～the Apremilast slow release of embodiment 5 preparation
50% and 80% release time of the Apremilast implant of implant and comparative example 1～comparative example 2 preparation, Fig. 4 is the application
The release profiles of the Apremilast sustained-release implant of embodiment 4 preparation.
Embodiment 5
Raw material:
Preparation method is with embodiment 1.
Experimental result is shown in Table 1 and Fig. 5, and wherein, table 1 is the embodiment of the present application 1～the Apremilast slow release of embodiment 5 preparation
50% and 80% release time of the Apremilast implant of implant and comparative example 1～comparative example 2 preparation, Fig. 5 is the application
The release profiles of the Apremilast sustained-release implant of embodiment 5 preparation.
By above-described embodiment, when principal agent maintains the content of 30%, remaining component becomes in the range of this setting
Change can preferably meet the requirement of implant release medicine.And the rate of release of embodiment 1～3 there was no significant difference.
By embodiment 3, embodiment 4 and the embodiment 5 mensuration by release in vitro condition, along with Apremilast contains
The raising of amount, the rate of release of this product slightly improves, but the measurement result of all releases changes and there was no significant difference, and says
Bright this product prescription selects weight range that the release of prescription is had preferable controlled range.
Comparative example 1
Raw material:
Preparation method:
By the PLGA (wherein containing lactide 80%, Acetic acid, hydroxy-, bimol. cyclic ester 20%) and two that molecular weight is 50000
Poly-propyl ester-Polyethylene Glycol the di-block copolymer of block molecule amount respectively 50000 and 2000 is dissolved in dichloromethane, and adds
5 Spans 80, stir.After addition Apremilast, Polyethylene Glycol under 8000 turns/min, high-speed stirred emulsifying 5min,
To suspension.Above-mentioned suspension is joined in 5% aqueous gelatin solution, and 8000 turns/min stirs 5min, obtains oil-in-water Bao Gu
Body powder emulsion.Stirring 5h under room temperature, solvent flashing, with distilled water wash, lyophilization final vacuum is dried, and obtains Apremilast
Microgranule, prepares Apremilast sustained-release implant after sterilizing.
Experimental result is shown in Table 1 and Fig. 6, and wherein, table 1 is the embodiment of the present application 1～the Apremilast slow release of embodiment 5 preparation
50% and 80% release time of the Apremilast implant of implant and comparative example 1～comparative example 2 preparation, Fig. 6 is the application
The release profiles of the Apremilast sustained-release implant of comparative example 1 preparation.
Comparative example 2
Raw material:
Preparation method is with comparative example 1.
Experimental result is shown in Table 1 and Fig. 7, and wherein, table 1 is the embodiment of the present application 1～the Apremilast slow release of embodiment 5 preparation
50% and 80% release time of the Apremilast implant of implant and comparative example 1～comparative example 2 preparation, Fig. 6 is the application
The release profiles of the Apremilast sustained-release implant of comparative example 2 preparation.
By the release ratio of embodiment and comparative example relatively, sustained-release implant prepared by the embodiment in the present invention is more right
Ratio has more preferable slow release effect.
Embodiment 6
Effect experiment
1 experiment material
1.1 Experimental agents
(1) test medicine: Apremilast implant.
(2) positive control medicine: Apremilast tablet.
(3) adjuvant tester: polylactic acid (PLA), PLGA (PLGA) and Polyethylene Glycol
6000, it is prepared as microgranule implant.
1.2 laboratory animals: SCID nude mouse, 18～20g, male, 4 week old.
1.3 diseased mice sources: xenograft model.
2, experimental technique
2.1 pass through manual method, and collection psoriatic's active stage skin transplantation, in SCID mice back epidermis, filters out
Meet the row stochastic packet of going forward side by side of the mice of requirement of experiment to be administered.Medication is that Apremilast above example prepared is planted
Enter agent or adjuvant comparison implant injects intramuscular at mice transplanting.Positive control Apremilast tablet gastric infusion.
2.2 packets and administration
(1) animal packet is arranged with dosage
Mice is randomly divided into adjuvant matched group, positive controls, test medicine group.Test medicine group uses successively relatively
Implant prepared by five embodiments answered and two comparative examples, number of animals is often to organize 6.Adjuvant control animals number is 12
Only.Positive controls fills and is fed for giving Apremilast 5mg/kg, BID, and number of animals is 6.
(2) it is administered
GP TH during modeling 10 days.
Test medicine group uses according to each comparative example in each embodiment in embodiment 1～5 and comparative example 1～2
6 experiment mices of random packet, inject drug delivery implant.
Positive controls (n=6), uses gavage to give Apremilast tablet.
Adjuvant matched group (n=12), injects blank implant.
2.3 observation index
Observe the general status of animal, food-intake during test, periodically weigh, and routine observation mouse skin change feelings
Condition.
2.4 evaluation criterions and time:
Measuring the treatment rate of each treatment group after being administered 4 weeks, assay method is as follows:
Treatment rate=(adjuvant matched group average diseased epidermis area-treatment group group average diseased epidermis area)/adjuvant pair
According to organizing average diseased epidermis area × 100%,.
3 result of the tests
According to above example 1～5 and comparative example 1～2 in certain Apremilast amount ranges all to treatment group
Mouse skin psoriasis has significantly treatment or inhibitory action, although various dose all can effectively suppress mouse skin to fall ill,
But being as the treatment rate of release that Apremilast implant is different, mouse skin serviceability rate has certain diversity.Embodiment 1
～5 and comparative example 1～2 treatment group mice the ill area of epidermis compared to start to occur lesion area decrease 40.34%,
45.89%, 50.99%, 59.87%, 60.94% and 34.05%, 38.41%；Compare with model group, embodiment 1～5 and right
Ratio 1～2 groups of ill suppression ratio of epidermis have certain diversity.Each group mouse skin treatment rate compares and see table 2.
The comparison of Mouse Weight, dermal treatment rate etc. respectively organized by table 2
4, interpretation of result
This experimental result display Apremilast implant severe combined immunodeficiency (SCID) to using Transplanted Human skin
Mouse model demonstrates good therapeutic effect, and Apremilast oral tablet is had more excellent therapeutic effect, try simultaneously
Yan Ge group is showed no overt toxicity reaction.
From above-described embodiment, Apremilast sustained-release implant prepared by the present invention has the slow release effect of excellence.Point
Not compared with comparative example, the embodiment of Apremilast sustained-release implant relatively comparative example has more preferable therapeutic effect.
Apremilast sustained-release implant prepared by the present invention, compared with Apremilast oral tablet, has similar effect,
But the sustained-release implant of the present invention has administration number of times, and few and final therapeutic effect is more excellent, uses general technical method complete
The Apremilast implant become can not reach equal therapeutic effect.
The explanation of above example is only intended to help to understand method and the core concept thereof of the present invention.It is right to it should be pointed out that,
For those skilled in the art, under the premise without departing from the principles of the invention, it is also possible to the present invention is carried out
Some improvement and modification, these improve and modify in the protection domain also falling into the claims in the present invention.
Claims (10)
1. an Apremilast sustained-release implant, including:
Above-mentioned each component total content is 100%.
Apremilast sustained-release implant the most according to claim 1, it is characterised in that described polylactic acid content is 5wt%
～10wt%.
Apremilast sustained-release implant the most according to claim 1, it is characterised in that described polyglycolic-polylactic acid
Copolymer level is 40wt%～60wt%.
Apremilast sustained-release implant the most according to claim 1, it is characterised in that described polyethylene glycol 6000 content is
5wt%～10wt%.
5. a preparation method for Apremilast sustained-release implant, including:
A) Apremilast, polylactic acid, PLGA, polyethylene glycol 6000 are dissolved in dichloromethane,
Obtain solution；
B) by step A) solution that obtains mixes with poly-vinyl alcohol solution, sequentially passes through high-speed stirred, stirring at low speed, centrifugal collect
Microgranule, is dried, obtains Apremilast sustained-release implant；
Described Apremilast, polylactic acid, PLGA, the mass ratio of polyethylene glycol 6000 be (30～
40): (0～20): (30～60): (0～10).
Preparation method the most according to claim 5, it is characterised in that described step B) in, by step A) solution that obtains
Mix with poly-vinyl alcohol solution particularly as follows:
By step A) solution that obtains is added drop-wise in poly-vinyl alcohol solution.
Preparation method the most according to claim 5, it is characterised in that the rotating speed of described high-speed stirred is 6000～10000
Turn/min.
Preparation method the most according to claim 5, it is characterised in that the rotating speed of described stirring at low speed is 50～100 turns/
min。
9. according to the preparation method described in claim 5, it is characterised in that described step B) in, described be dried particularly as follows:
Lyophilization, is then vacuum dried.
10. described in any one of the Apremilast sustained-release implant described in any one of Claims 1 to 4, or claim 5～9
The arthritic medicine that the Apremilast sustained-release implant that preparation method prepares causes at preparation treatment psoriasis or psoriasis
Application in thing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510957710.8A CN105935350B (en) | 2015-12-18 | 2015-12-18 | A kind of Apremilast sustained-release implant and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510957710.8A CN105935350B (en) | 2015-12-18 | 2015-12-18 | A kind of Apremilast sustained-release implant and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105935350A true CN105935350A (en) | 2016-09-14 |
| CN105935350B CN105935350B (en) | 2018-11-16 |
Family
ID=57152866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510957710.8A Active CN105935350B (en) | 2015-12-18 | 2015-12-18 | A kind of Apremilast sustained-release implant and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105935350B (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686118A (en) * | 2005-04-07 | 2005-10-26 | 中国人民解放军第二军医大学 | Tiemozolenium brain slow release implantation agent and its preparation method |
| CN101732345A (en) * | 2008-11-20 | 2010-06-16 | 中国人民解放军第二军医大学 | Cisplatin spinal tumor slow-release implant and preparation method thereof |
| CN104546831A (en) * | 2014-12-30 | 2015-04-29 | 杭州新博思生物医药有限公司 | Medicine composition containing apremilast |
| CN104761484A (en) * | 2014-11-24 | 2015-07-08 | 上海优拓医药科技有限公司 | A stable Apremilast crystal form II free of solvates and a preparing method thereof |
| CN104792913A (en) * | 2015-05-18 | 2015-07-22 | 苏州亚宝药物研发有限公司 | Separation detection method of apremilast and apremilast enantiomer |
| CN105004693A (en) * | 2015-08-22 | 2015-10-28 | 南京海纳医药科技有限公司 | Tablets containing Apremilast active ingredients and vitro dissolution determination method thereof |
| CN105050624A (en) * | 2013-03-14 | 2015-11-11 | 细胞基因公司 | Treatment of psoriatic arthritis using apremilast |
| CN105919927A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Apremilast oral liquid and preparation method thereof |
| CN107405311A (en) * | 2015-12-24 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | Apremilast sustained release preparation |
-
2015
- 2015-12-18 CN CN201510957710.8A patent/CN105935350B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686118A (en) * | 2005-04-07 | 2005-10-26 | 中国人民解放军第二军医大学 | Tiemozolenium brain slow release implantation agent and its preparation method |
| CN101732345A (en) * | 2008-11-20 | 2010-06-16 | 中国人民解放军第二军医大学 | Cisplatin spinal tumor slow-release implant and preparation method thereof |
| CN105050624A (en) * | 2013-03-14 | 2015-11-11 | 细胞基因公司 | Treatment of psoriatic arthritis using apremilast |
| CN104761484A (en) * | 2014-11-24 | 2015-07-08 | 上海优拓医药科技有限公司 | A stable Apremilast crystal form II free of solvates and a preparing method thereof |
| CN104761484B (en) * | 2014-11-24 | 2018-03-27 | 上海优拓医药科技有限公司 | A kind of A Pusite crystal formations II without solvate of stabilization and preparation method thereof |
| CN104546831A (en) * | 2014-12-30 | 2015-04-29 | 杭州新博思生物医药有限公司 | Medicine composition containing apremilast |
| CN104792913A (en) * | 2015-05-18 | 2015-07-22 | 苏州亚宝药物研发有限公司 | Separation detection method of apremilast and apremilast enantiomer |
| CN105004693A (en) * | 2015-08-22 | 2015-10-28 | 南京海纳医药科技有限公司 | Tablets containing Apremilast active ingredients and vitro dissolution determination method thereof |
| CN105919927A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Apremilast oral liquid and preparation method thereof |
| CN107405311A (en) * | 2015-12-24 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | Apremilast sustained release preparation |
Non-Patent Citations (1)
| Title |
|---|
| PH SCHAFER，ET AL: ""Apremilast, a cAMP phosphodiesterase-4 inhibitor,"", 《BRITISH JOURNAL OF PHARMACOLOGY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105935350B (en) | 2018-11-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105517536B (en) | The sustained-release composition of injectable and its for treatment of arthritis disease and ache related method | |
| KR20090014300A (en) | Water solution of 20(r)-ginsenoside rg3 pharmaceutical composition and process thereof | |
| CN107530276A (en) | Use the method for biodegradable fibrous material of the Electrospun manufacture containing medicine | |
| CN108815160A (en) | A kind of rapamycin liposome nano granule and preparation method thereof | |
| EP3021811A1 (en) | Method of pre-preparing medications for therapeutic uses | |
| CN103330680A (en) | Nano drug transdermal preparation and preparation method thereof | |
| CN102579365B (en) | Risperidone microsphere preparation and preparation method thereof | |
| CN102188439A (en) | Nanoparticle liposome for releasing different medicines in programmed manner and preparation and use thereof | |
| CN102048712A (en) | Stable film agent medicinal composition containing allergen and preparation method thereof | |
| CN105997889B (en) | A kind of subcutaneous injection Amifostine sustained-release micro-spheres and preparation method thereof | |
| CN103830170B (en) | Ivermectin is at body gel injection and preparation method thereof | |
| CN102631667B (en) | Nerve regeneration promotion injection and preparation method thereof | |
| CN105935350A (en) | Apremilast sustained-release implant and preparation method thereof | |
| CN102724969A (en) | A human factor IX slow release dosage form | |
| CN109496152A (en) | The method of the intramuscular inventory and its prevention and treatment of deccox composition | |
| CN105106937A (en) | Application of nerve growth factor in preparation of drug used for promoting healing of fresh skin wound | |
| CN101756909A (en) | Lung-targeting ceftiofur microsphere and preparation method thereof | |
| CN101549177B (en) | Medicament coating applied to fixation screw in rachis, preparation method thereof and application thereof | |
| CN104688722B (en) | Purposes of the epimedium aglucone in preparation prevention or treatment bone marrow suppression drug | |
| CN101716352B (en) | Antisense oligonucleotide nano preparation resisting middle-period factor, preparation and application thereof | |
| CN101385718B (en) | Osmotic pump preparation composition for treating hyperlipemia | |
| CN104922085A (en) | Risperidone implant and preparation method for same | |
| Liu et al. | Preparation of Polylactic Acid/Glycolic Acid Copolymer Nanoparticles and Its Effect in the Treatment of Diabetes | |
| CN104688762A (en) | Medicinal composition containing 12 vitamins and used for intravenous injection | |
| CN107802598A (en) | A kind of nano medicament carrying system of equisetin and its derivative and preparation method thereof and the application in skin soft-tissue infection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |