CN108771656A - Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application - Google Patents
Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application Download PDFInfo
- Publication number
- CN108771656A CN108771656A CN201810754778.XA CN201810754778A CN108771656A CN 108771656 A CN108771656 A CN 108771656A CN 201810754778 A CN201810754778 A CN 201810754778A CN 108771656 A CN108771656 A CN 108771656A
- Authority
- CN
- China
- Prior art keywords
- rapamycin
- release
- slow
- sustained
- release dosage
- 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
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application, be related to pharmaceutical technology field, rapamycin sustained-release dosage type provided by the invention, including mass ratio be 1:The rapamycin and slow-release material of 10-50.Its medicament contg is high, can play the role of medicament slow release, controlled release, can effectively alleviate and treat osteoarthritis.The preparation method of rapamycin sustained-release dosage type provided by the invention, method is easy to operate, and the rapamycin sustained-release dosage type being prepared has good stability, and internal residence time length, bioavilability are high, are conducive to the popularization and application of industrialized production.Rapamycin provided by the invention is slow-release injected, it can be without the help of organic solvent direct injection, reduce the adverse reaction brought due to organic solvent and safety accident, and retention time is long in vivo, it is injected without being repeated several times, the cost for reducing multiple dosing, reduces the feeling of pain and irritation of patient.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly, to a kind of rapamycin sustained-release dosage type and preparation method, thunder pa
Mycin is slow-release injected and applies.
Background technology
Osteoarthritis (OA) is also referred to as degenerative arthritis, is the most common disease in the elderly and overweight people.OA is
The disease in joint, but unlike that rheumatoid arthritis (RA), this disease is not systematic, usually only influence one or
Several joints.This disease causes total destruction of articular cartilage, the hardening of lower section bone and spur to be formed, and causes locomitivity
Forfeiture and pain.Final result often needs total joint replacement.
World Health Organization's investigation finds that the whole world has 10% male and 18% women to suffer from different degrees of OA,
Just there is 1 people to suffer from OA in Asia, every 6 people, and China OA patient is more than 100,000,000 at present, and as China human mortality is old
The aggravation in age, this data are in the trend risen year by year.
Pain caused by OA and the inconvenient daily life quality for not only influencing patient, being up to 53% disability rate more makes it
The number one killer disabled as the mankind.Rise year by year in the correlative charges of western developed country, knee osteoarthritis diagnosis and treatment, accounts for about state
The 1-2.5% of people's total output value brings heavy financial burden to patient and society.The generation of OA is related with many factors,
Including age, gender, heredity, obesity and wound etc..
OA drugs clinically at present, treat the symptom of OA rather than disease itself.Alleviate the common drug packet of OA symptoms
Include nonsteroidal anti-inflammatory drug (NSAID), non-narcotic analgestic, narcotic analgesics and glucocorticoid etc..Therefore, for treating OA
There are the unsatisfied medical demands of height.And for treating the drug of OA, such as rapamycin is hydrophobic drug, Bu Nengzhi
Injection is connect, needs just inject using organic solvent such as DMSO dissolvings, but organic solvent has toxicity, can bring not to patient
Evitable toxic side effect.In addition, there is also drug retention time is short, need that the problem of injecting is repeated several times.
In view of this, special propose the present invention.
Invention content
First of the present invention is designed to provide a kind of rapamycin sustained-release dosage type, existing in the prior art to alleviate
Rapamycin retention time is short, needs that the technical issues of injecting is repeated several times.
Second object of the present invention is to provide the preparation method of above-mentioned rapamycin sustained-release dosage type, this method operation letter
Single, convenient and efficient, the rapamycin sustained-release dosage type being prepared has good stability, and is conducive to industrialized production.
Third object of the present invention is to provide a kind of rapamycin slow-release injected, alleviates thunder pa in the prior art
Mycin needs just inject using organic solvent such as DMSO dissolvings, inevitable toxic side effect can be brought to patient, and protect
It stays the time short, needs that the technical issues of injecting is repeated several times.
Fourth object of the present invention be to provide above-mentioned rapamycin sustained-release dosage type or rapamycin it is slow-release injected
Inhibit the application in mTORC1.
The present invention the 5th be designed to provide above-mentioned rapamycin sustained-release dosage type or rapamycin it is slow-release injected
Prepare the application in the drug for the treatment of osteoarthritis.
The present invention provides a kind of rapamycin sustained-release dosage type, the rapamycin sustained-release dosage type includes：Rapamycin and
Slow-release material；
Wherein, the mass ratio of the rapamycin and the slow-release material is 1:10-50.
Further, the rapamycin further includes rapamycin derivative and forms of rapamycin analogs.
Further, the slow-release material includes polymeric alloy membrane and small molecule slow-release material；
Preferably, the polymeric alloy membrane is selected from sodium alginate, chitosan, Poly(D,L-lactide-co-glycolide, gathers
Caprolactone, polylactic acid, polytrimethylene carbonate, polyglycolic acid, poly butyric ester, the copolymerization of polyhydroxybutyrate hydroxypentanoic acid
It is one or more in object, polyorthoester and polyanhydride；
Preferably, the small molecule slow-release material includes lipoid substance, preferably lipoid, more preferably phosphatide and/or
Steroids.
Preferably, the weight average molecular weight of the polymeric alloy membrane is 10000-100000 dalton, preferably
10000-80000 dalton, more preferably 10000-50000 dalton.
Further, further include emulsifier, preferably hydrophilic emulsifier；
Preferably, the emulsifier is selected from polyvinyl alcohol, Tween 80, PEG-100 stearates, stearine, flower
It is one or more in raw alcohol, fatty alcohol polyoxyethylene ether, Compritol 888 ATO or cetearyl glucoside.
The present invention also provides the preparation method of above-mentioned rapamycin sustained-release dosage type, the preparation method includes：
The organic solution for providing the rapamycin and slow-release material of formula ratio, is uniformly mixed with emulsifier, and removal is organic molten
After agent, the rapamycin sustained-release dosage type is obtained.
Further, the boiling point of the organic solvent is not higher than 50 DEG C；
Preferably, the organic solvent is selected from acetone, chloroform, methylamine, dimethylamine, ether, pentane, dichloromethane or two sulphur
Change one or more in carbon.
Further, the organic solution is to have in 0.1-2mL with 0.1-2mg rapamycins per 10-30mg slow-release materials
Dissolving obtains in solvent；
Preferably, it is mixed with 1-10mL emulsifiers per 0.1-2mL organic solvents；
Preferably, the slow-release material is poly lactic-co-glycolic acid, and the organic solvent is dichloromethane, the emulsification
Agent is 1% (w/v) polyvinyl alcohol.
The present invention also provides a kind of rapamycin is slow-release injected, including above-mentioned rapamycin sustained-release dosage type or application
The rapamycin sustained-release dosage type and solvent that above-mentioned preparation method is prepared.
The thunder being prepared the present invention also provides above-mentioned rapamycin sustained-release dosage type or using above-mentioned preparation method
Pa mycin sustained-release dosage type or the slow-release injected application in inhibiting mTORC1 of above-mentioned rapamycin.
In addition, being prepared the present invention also provides above-mentioned rapamycin sustained-release dosage type or using above-mentioned preparation method
Rapamycin sustained-release dosage type or above-mentioned rapamycin it is slow-release injected prepare treatment osteoarthritis drug in application.
Rapamycin sustained-release dosage type provided by the invention, including mass ratio are 1:The rapamycin and slow-release material of 10-50.
The rapamycin sustained-release dosage type medicament contg is high, and use is small, can play the role of medicament slow release, controlled release.Meanwhile the thunder
Pa mycin sustained-release dosage type action target spot understands, by inhibiting mTORC1, can effectively alleviate and treat osteoarthritis.Also,
By the encapsulating of slow-release material, enable to administering rapamycin that longer therapeutic effect, reduction is once just maintained repeatedly to give
The cost of medicine reduces the feeling of pain and irritation of patient, reduces the adverse reaction brought due to organic solvent and safe thing
Therefore.
The preparation method of above-mentioned rapamycin sustained-release dosage type provided by the invention, provides the rapamycin and sustained release of formula ratio
The organic solution of material, is uniformly mixed with emulsifier, and after removing organic solvent, rapamycin sustained-release dosage type is made.This method is grasped
Make simply, convenient and efficient, the rapamycin sustained-release dosage type being prepared has good stability, the internal residence time is long, drug release property is good,
Bioavilability is high, is conducive to the popularization and application of industrialized production.
Rapamycin provided by the invention is slow-release injected, including above-mentioned rapamycin sustained-release dosage type and solvent, can
Without the help of organic solvent direct injection, the adverse reaction brought due to organic solvent and safety accident are reduced, and in vivo
Retention time is long, it is not necessary that injection is repeated several times, reduces the cost of multiple dosing, reduces the feeling of pain and irritation of patient.
Description of the drawings
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art are briefly described, it should be apparent that, in being described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, other drawings may also be obtained based on these drawings.
Figure 1A is the coloration result figure for the postoperative 4 weeks OA of DMM model mices that experimental example 1 of the present invention provides；
Figure 1B is that the rapamycin sustained-release dosage type that experimental example 1 of the present invention provides is small by mTROC1 target treatment DMM models
The coloration result figure of the postoperative 4 weeks OA of mouse；
Fig. 1 C are the coloration result figure for the postoperative 8 weeks OA of DMM model mices that experimental example 1 of the present invention provides；
Fig. 1 D are that the rapamycin sustained-release dosage type that experimental example 1 of the present invention provides is small by mTROC1 target treatment DMM models
The coloration result figure of the postoperative 8 weeks OA of mouse；
Fig. 2A scored for postoperative 4 weeks that experimental example 1 of the present invention provides according to the OARSI of safranin O-Fast Green stain；
Fig. 2 B scored for postoperative 8 weeks that experimental example 1 of the present invention provides according to the OARSI of safranin O-Fast Green stain；
Fig. 3 A are the coloration result figure for the postoperative 4 weeks OA of ACLT model mices that experimental example 2 of the present invention provides；
Fig. 3 B are that the rapamycin sustained-release dosage type that experimental example 2 of the present invention provides is small by mTROC1 target treatment ACLT models
The coloration result figure of the postoperative 4 weeks OA of mouse；
Fig. 3 C are the coloration result figure for the postoperative 8 weeks OA of ACLT model mices that experimental example 2 of the present invention provides；
Fig. 3 D are that the rapamycin sustained-release dosage type that experimental example 2 of the present invention provides is small by mTROC1 target treatment ACLT models
The coloration result figure of the postoperative 8 weeks OA of mouse；
Fig. 3 E are the coloration result figure for the ACLT model mice 12 weeks after operation OA that experimental example 2 of the present invention provides；
Fig. 3 F are that the rapamycin sustained-release dosage type that experimental example 2 of the present invention provides is small by mTROC1 target treatment ACLT models
The coloration result figure of mouse 12 weeks after operation OA；
Fig. 4 A scored for postoperative 4 weeks that experimental example 2 of the present invention provides according to the OARSI of safranin O-Fast Green stain；
Fig. 4 B scored for postoperative 8 weeks that experimental example 2 of the present invention provides according to the OARSI of safranin O-Fast Green stain；
Fig. 4 C are that the 12 weeks after operation that experimental example 2 of the present invention provides scores according to the OARSI of safranin O-Fast Green stain.
Specific implementation mode
Unless otherwise defined herein, the scientific and technical terms used together with the present invention should have ordinary skill people
The normally understood meaning of member.The meaning and scope of term should be clear, however, in the case of any potential ambiguity, this
The definition that text provides is prior to any dictionary or external definition.In this application, unless otherwise indicated, the use of "or" means
"and/or".In addition, the use of term " comprising " and other forms is non-limiting.
Unless otherwise indicated, methods and techniques of the invention generally according to it is well known in the art that and as various with
It is carried out referring more particularly to the conventional method described in document, the bibliography is quoted and begged for from beginning to end in this specification
By.The nomenclature used together with medicine described herein and pharmaceutical chemistry and its laboratory procedure and technology are this field crowds
It is those of well known and usually used.
The present invention provides a kind of rapamycin sustained-release dosage types, including：Rapamycin and slow-release material.
Rapamycin (RAPA) molecular formula is C51H79NO13, it is white crystalline solid, fusing point is 183-185 DEG C, lipophilicity,
The organic solvents such as methanol, ethyl alcohol, acetone, chloroform are dissolved in, it is atomic to be dissolved in water, it is practically insoluble in ether.Its chemical structural formula is such as
Shown in formula (I)：
Slow-release material is to refer to by delaying drug from the rate of releasing drug in the dosage form, reduces the suction that drug enters body
Rate is received, to play the material of more preferably therapeutic effect.In the present invention, rapamycin passes through the encapsulating of slow-release material, energy
The rate of releasing drug for enough delaying rapamycin is administered once and just maintains longer therapeutic effect, reduces the cost of multiple dosing, drop
The low feeling of pain and irritation of patient.
Wherein, the mass ratio of rapamycin and slow-release material is 1:10-50, such as can be, but it is not limited to 1:10,1:
20,1:30,1:40 or 1:50.When the mass ratio of rapamycin and slow-release material is 1:When within the scope of 10-50, obtained thunder pa is mould
Plain sustained-release dosage type has good stability, and the internal residence time is long, drug release property is good, bioavilability is high.
Preferably, the mass ratio of rapamycin and slow-release material is 1:10-30, more preferably 1:20.When rapamycin with
The mass ratio of slow-release material is 1:When 20, obtained rapamycin sustained-release dosage type stability is more preferable, and the internal residence time is longer, releases
Pharmacological property is more preferable, bioavilability higher.
Rapamycin sustained-release dosage type provided by the invention, medicament contg are high, and use is small, can play medicament slow release,
The effect of controlled release.Meanwhile the rapamycin sustained-release dosage type action target spot understands, by inhibiting mTORC1, can effectively alleviate
With treatment osteoarthritis.Also, by the encapsulating of slow-release material, administering rapamycin is enabled to once just to remain longer
Therapeutic effect reduces the cost of multiple dosing, reduces the feeling of pain and irritation of patient, reduces since organic solvent is brought
Adverse reaction and safety accident.
In some preferred embodiments, rapamycin further includes rapamycin derivative and forms of rapamycin analogs.
In some preferred embodiments, slow-release material includes polymeric alloy membrane and small molecule slow-release material.
Preferably, polymeric alloy membrane is selected from sodium alginate, chitosan, Poly(D,L-lactide-co-glycolide, gathers in oneself
Ester, polylactic acid, polytrimethylene carbonate, polyglycolic acid, poly butyric ester, polyhydroxybutyrate hydroxyl pentanoate copolymer,
It is one or more in polyorthoester and polyanhydride；
Preferably, small molecule slow-release material includes lipoid substance, preferably lipoid, and more preferably phosphatide and/or class are solid
Alcohol.
Wherein, phosphatide for example can be, but be not limited to lecithin, sphingomyelins, cephalin, phosphatidylserine, phosphatidyl
It is one or more in glycerine, diphosphatidylglycerol or phosphatidylinositols；Steroids for example can be, but be not limited to cholesterol,
It is one or more in sitosterol, stigmasterol, ergosterol or derivatives thereof.
It is highly preferred that slow-release material is Poly(D,L-lactide-co-glycolide.
Poly(D,L-lactide-co-glycolide (poly (lactic-co-glycolic acid), PLGA) is by two kinds of lists
Body --- lactic acid and hydroxyacetic acid are polymerized at random, are a kind of degradable functional polymer organic compounds, have good
Biocompatibility, nontoxic, good encystation and film forming performance.When slow-release material is selected as poly lactic-co-glycolic acid copolymerization
When object, obtained rapamycin sustained-release dosage type has superior stability and drug release property.
In some preferred embodiments, the weight average molecular weight of polymeric alloy membrane is 10000-100000 dongles
, such as can be, but it is not limited to 10000 dalton, 20000 dalton, 30000 dalton, 40000 dalton, 50000
Er Dun, 60000 dalton, 70000 dalton, 80000 dalton, 90000 dalton or 100000 dalton, preferably
10000-80000 dalton, more preferably 10000-50000 dalton.
The molecular weight of slow-release material can be according to being palliative processing or therapeutic treatment and difference.In palliative application
In, it gives relatively low dosage for a long time with the interval of rather low-frequency rate, that is, needs the sustained release period of rapamycin longer, at this point,
The slow-release material that molecular weight can be selected larger.In therapeutic application, it is sometimes desirable to be given with relatively short interval relatively high
Dosage need the sustained release period of rapamycin relatively short until the progress of disease is delayed or stops, at this point it is possible to
The slow-release material for selecting molecular weight smaller.
In some preferred embodiments, further include emulsifier, preferably hydrophilic emulsifier.
Emulsifier is can to improve the various surface tension constituted between phase in emulsion, is allowed to form uniform and stable point
The substance of granular media system or emulsion.In the present invention, rapamycin and slow-release material are emulsified using emulsifier so that thunder
Pa mycin achieve the purpose that can direct injection, reduce the adverse reaction brought due to organic solvent and safety accident.
Preferably, emulsifier be selected from polyvinyl alcohol, Tween 80, PEG-100 stearates, stearine, arachidic alcohol,
It is one or more in fatty alcohol polyoxyethylene ether, Compritol 888 ATO or cetearyl glucoside, it is highly preferred that emulsifier
For polyvinyl alcohol.Rapamycin and slow-release material are emulsified using polyvinyl alcohol so that rapamycin reaches can be direct
The purpose of injection reduces the adverse reaction brought due to organic solvent and safety accident.
The present invention also provides the preparation methods of above-mentioned rapamycin sustained-release dosage type, including：
The organic solution for providing the rapamycin and slow-release material of formula ratio, is uniformly mixed with emulsifier, and removal is organic molten
After agent, rapamycin sustained-release dosage type is obtained.
The preparation method of above-mentioned rapamycin sustained-release dosage type provided by the invention, it is easy to operate, it is convenient and efficient, it is prepared
Rapamycin sustained-release dosage type have good stability, internal residence time is long, drug release property is good, bioavilability is high, is conducive to industrialization
The popularization and application of production.
In some preferred embodiments, the boiling point of organic solvent is not higher than 50 DEG C.
The boiling point of organic solvent is not higher than 50 DEG C, can ensure during follow-up removal, be by room temperature or low-grade fever
It can evaporate, avoid the purifications such as distillation, extraction except miscellaneous operation keeps preparation process easier on the basis of ensureing effect.
Preferably, organic solvent is selected from acetone, chloroform, methylamine, dimethylamine, ether, pentane, dichloromethane or carbon disulfide
In it is one or more, it is highly preferred that organic solvent be selected from dichloromethane.
Dichloromethane volatility is good, and toxicity is low.It selects dichloromethane as organic solvent, can utmostly reduce poison
Side effect.
In some preferred embodiments, organic solution is to exist with 0.1-2mg rapamycins per 10-30mg slow-release materials
Dissolving obtains in 0.1-2mL organic solvents.
Wherein, slow-release material for example can be, but be not limited to 10mg, 15mg, 20mg, 25mg or 30mg, rapamycin example
Such as can be, but be not limited to 0.1mg, 0.5mg, 1mg, 1.5mg or 2mg, organic solvent for example can be, but be not limited to 0.1mL,
0.5mL, 1mL, 1.5mL or 2mL.
Preferably, it is mixed with 1-10mL emulsifiers per 0.1-2mL organic solvents.
Wherein, emulsifier for example can be, but be not limited to 1mL, 2mL, 3mL, 4mL, 5mL, 6mL, 7mL, 8mL, 9mL or
10mL。
Preferably, slow-release material is poly lactic-co-glycolic acid, and organic solvent is dichloromethane, and emulsifier is 1% (w/v)
Polyvinyl alcohol.
In some preferred embodiments, by stirring or ultrasound method be uniformly mixed, preferably rapamycin and
The organic solution of slow-release material utilizes magnetic agitation, is mixed with emulsifier and utilizes ultrasound.
In some preferred embodiments, organic solvent is removed using the method for natural evaporation.
In some preferred embodiments, after removing organic solvent, centrifuge and collect rapamycin and slow-release material
Copolymer, the copolymer can be microballoon, or nano particle.
The present invention also provides a kind of rapamycin is slow-release injected, including above-mentioned rapamycin sustained-release dosage type or application
The rapamycin sustained-release dosage type and solvent that above-mentioned preparation method is prepared.
Wherein, injection may include carrier, be solvent or decentralized medium.Suitable carrier includes water, physiological saline, suppression
Bacterium water, phosphate buffered saline (PBS), ethyl alcohol, polyalcohol and its mixture and macromolecule micelle.These compositions must be sterile
And the liquid that is injectable.
Preferably, during the rapamycin is slow-release injected, rapamycin content is 400-500 μ g/mL, such as can be with
For, but it is not limited to 400 μ g/mL, 420 μ g/mL, 450 μ g/mL, 480 μ g/mL or 500 μ g/mL.
Rapamycin provided by the invention is slow-release injected, can without the help of organic solvent direct injection, reduce by
The adverse reaction brought in organic solvent and safety accident, and retention time is long in vivo, it is not necessary that injection is repeated several times, reduces
The cost of multiple dosing reduces the feeling of pain and irritation of patient.
The thunder being prepared the present invention also provides above-mentioned rapamycin sustained-release dosage type or using above-mentioned preparation method
Pa mycin sustained-release dosage type or the slow-release injected application in inhibiting mTORC1 of above-mentioned rapamycin.
MTOR (mammalian target of rapamycin) is a kind of serine/threonine kinase.Nutrition, growth
The factor stress wait signals that can activate mTORC1 (mTOR complex1), the translation of regulatory protein matter, ribosomes biosynthesis, cell
The various biologicals function such as growing multiplication, metabolism and aging.The OA therapy targets that mTORC1 is to determine, mTORC1 activation are closed in bone
Scorching various pathological changes are saved, including articular cartilage aging regression is formed with destruction, subchondral bone hyperplasia and spur, blood vessel shape
At playing an important role during, synovial membrane inflammation etc., inhibit mTORC1 activation or knock out mTORC1 can be effectively relieved above-mentioned symptom with
Delay osteoarthritis progression.Rapamycin sustained-release dosage type provided by the invention or rapamycin are slow-release injected, and action target spot is clear
Chu can effectively be treated and relief from osteoarthritis by inhibiting mTORC1.
In addition, being prepared the present invention also provides above-mentioned rapamycin sustained-release dosage type or using above-mentioned preparation method
Rapamycin sustained-release dosage type or above-mentioned rapamycin it is slow-release injected prepare treatment osteoarthritis drug in application.
In addition, the composition delivered according to the method for the present invention may include additional or second medicament, such as organic two phosphorus
Hydrochlorate, chemotherapeutic agents, radiopharmaceutical agent, TNF- antagonists, nonsteroid anti-inflammatory drugs agent, steroids, antioxidant, angiogenesis
Inhibitor, Matrix Metalloproteinase Inhibitors, vitamin, selective estrogen receptor modulators, Estrogen-Progestin, androgen,
Calcitonin, antibiotic, cathepsin K inhibitor, inhibin, integrin receptor antagonists, osteoblast anabolic agent
Or or mixtures thereof selective serotonin reuptake inhibithors, aminoglucose, hyaluronic acid.
It should be noted that can be according to " patient ", " patient " or " animal " of the illness of disclosed method treatment
The mankind or non-human mammal, therefore, " patient ", " patient " or " animal " of the illness can be the mankind and dog, cat,
Mouse, rat, ox, sheep, pig, goat or primate, and may include laboratory animal, livestock and domestic.
In order to contribute to it is clearer understand present disclosure, be described in detail as follows in conjunction with specific embodiment.
Unless otherwise instructed, the rapamycin used in the embodiment of the present invention, 99% or more purity, is purchased from
MedChemExpress companies.PLGA 50/50, molecular weight 30000,99% or more purity are purchased from Jinan Dai Gang companies.1,2-
Distearoyl-sn-glycero-3-phosphocholine (DSPC), DSPE-mPEG2000 are purchased from Avanti Polar
Lipids, cholesterol (Chol) are purchased from Sigma companies, and purity is 99% or more.Polycaprolactone (PCL) molecular weight 10000 is pure
99% or more degree is purchased from Sigma companies.
Embodiment 1
A kind of rapamycin sustained-release dosage type is present embodiments provided, including mass ratio is 1:20 rapamycin and poly- breast
Acid-co-glycolic acid (PLGA 50/50).It is prepared via a method which to obtain microballoon：
(1) 20mg PLGA and 1mg rapamycins are dissolved in 1mL dichloromethane (DCM)；
(2) prepare 1% polyvinyl alcohol of 6mL (PVA) solution, ultrapure water dissolution；
(3) (1) is poured into (2), magnetic agitation 30min；
(4) by (3) ultrasound 4min；
(5) under magnetic stirring, the organic solvent in natural evaporation (4)；
(6) (5) are centrifuged into 20min at room temperature, 12000g；
(7) microballoon is collected, twice with ultra-pure water rinse, freeze-drying preserves；
(8) it prepares 10mg/mL injectables PLGA and wraps up rapamycin dosage form, wherein rapamycin content is 450 μ g/mL.
Embodiment 2
A kind of rapamycin sustained-release dosage type is present embodiments provided, including mass ratio is 1:10 rapamycin and poly- breast
Acid-co-glycolic acid (PLGA 50/50).It is prepared via a method which to obtain microballoon：
(1) 10mg PLGA and 1mg rapamycins are dissolved in 1mL dichloromethane (DCM)；
(2) prepare 1% polyvinyl alcohol of 6mL (PVA) solution, ultrapure water dissolution；
(3) (1) is poured into (2), magnetic agitation 30min；
(4) by (3) ultrasound 4min；
(5) under magnetic stirring, the organic solvent in natural evaporation (4)；
(6) (5) are centrifuged into 20min at room temperature, 12000g；
(7) microballoon is collected, twice with ultra-pure water rinse, freeze-drying preserves；
(8) it prepares 10mg/mL injectables PLGA and wraps up rapamycin dosage form, wherein rapamycin content is 600 μ g/mL.
Embodiment 3
A kind of rapamycin sustained-release dosage type is present embodiments provided, including mass ratio is 1:50 rapamycin and poly- breast
Acid-co-glycolic acid (PLGA 50/50).It is prepared via a method which to obtain microballoon：
(1) 50mg PLGA and 1mg rapamycins are dissolved in 1mL dichloromethane (DCM)；
(2) prepare 1% polyvinyl alcohol of 6mL (PVA) solution, ultrapure water dissolution；
(3) (1) is poured into (2), magnetic agitation 30min；
(4) by (3) ultrasound 4min；
(5) under magnetic stirring, the organic solvent in natural evaporation (4)；
(6) (5) are centrifuged into 20min at room temperature, 12000g；
(7) microballoon is collected, twice with ultra-pure water rinse, freeze-drying preserves；
(8) it prepares 10mg/mL injectables PLGA and wraps up rapamycin dosage form, wherein rapamycin content is 180 μ g/mL.
Embodiment 4
A kind of rapamycin sustained-release dosage type is present embodiments provided, including mass ratio is 1:20 rapamycin and poly- breast
Acid-co-glycolic acid (PLGA 50/50).It is prepared via a method which to obtain nanoparticle：
(1) 20mg PLGA and 1mg rapamycins are dissolved in 1mL acetone；
(2) prepare 1% polyvinyl alcohol of 6mL (PVA) solution, ultrapure water dissolution；
(3) under magnetic stirring, (1) is poured into (2)；
(4) organic solvent in natural evaporation (3)；
(5) (4) are centrifuged into 20min at room temperature, 12000g；
(6) nanoparticle is collected, twice with ultra-pure water rinse, freeze-drying preserves；
(7) it prepares 10mg/mL injectables PLGA and wraps up rapamycin dosage form, wherein rapamycin content is 450 μ g/mL.
Embodiment 5
A kind of rapamycin sustained-release dosage type is present embodiments provided, including mass ratio is 1:10 rapamycin and DSPC/
Chol/DSPE-PEG.It is by Standard Thin film waterization and repeated film extrusion method liposome is prepared：
(1) in round-bottomed flask, by 10mg DSPC/Chol/DSPE-PEG2000 (6:4:1 molar ratio) and 1mg thunder pas
Mycin is dissolved in 5mL chloroforms；
At (2) 50 DEG C, decompression rotary evaporation 1h removes chloroform film forming；
(3) appropriate PBS is added, 60 DEG C of hydrated films prepare 10mg/mL rapamycin Liposomal dispersions；
(4) hand-held liposome extruder (LF-1, Avestin company) is utilized to prepare the lipid that grain size is 100nm or so
Somatocyst steeps；
(5) injectable liposome rapamycin dosage form, wherein rapamycin content are 700 μ g/mL.
Embodiment 6
A kind of rapamycin sustained-release dosage type is present embodiments provided, including mass ratio is 1:50 rapamycin and gather oneself in
Ester (PCL).It is prepared via a method which to obtain microballoon：
(1) 75mg PCL and 1mg rapamycins are dissolved in 5mL DCM；
(2) prepare 1% polyvinyl alcohol of 30mL (PVA) solution, ultrapure water dissolution；
(3) (1) is poured into (2)；
(4) under magnetic stirring, the organic solvent in natural evaporation (3)；
(5) (4) are centrifuged into 20min at room temperature, 12000g；
(6) microballoon is collected, twice with ultra-pure water rinse, freeze-drying preserves；
(7) it prepares 33.8mg/mL injectables PLGA and wraps up rapamycin dosage form, wherein rapamycin content is 450 μ g/
mL。
Comparative example 1
Rapamycin is dissolved in dimethyl sulfoxide (DMSO) (DMSO), 50mg/mL liquid storages are prepared.Liquid storage is diluted to PBS
10 μM of rapamycin injections (DMSO 0.02%).
Experimental example 1C57 mouse DMM model experiments
This experimental example by control group 1, model group 2, embodiment 1-5 groups and comparative example group group carry out zoopery, every group
10, concrete operations are as follows：
The C57 mouse big to 8-10 week old is injected intraperitoneally using 10% chloraldurate and carries out anaesthetic treatment, is fixed simultaneously
Disinfection.Experimental side is using on the inside of micro- blade cut patellar ligament, blunt separation muscle and fat pad etc., expose articular cavity and
Medial meniscus shin bone ligament.Medial meniscus ligament is cut off using micro- blade or microscissors, and on the inside of cut-out
Meniscus, then stop blooding and use normal saline flushing wound, layer-by-layer suture tissue and skin, structure mouse medial meniscus unstability
(DMM) model.Control sides are not further processed direct suture after opening skin exposure medial meniscus.It should be noted that avoiding in art
Injured joint cartilage, postoperative daily check wound, periodically giving penicillin intramuscular injection prevents from infecting, and knee joint is protected without fixation
It holds under normal feeding environment, animal can be voluntarily movable, ad lib drinking-water.
In addition to control group 1 and model group 2, corresponding rapamycin formulation is injected to experiment each group mouse respectively.Wherein, real
Applying the rapamycin sustained-release dosage type that a 1-6 is provided, 10 μ L, injection in every 4 weeks are primary every time；The injection every time 10 that comparative example 1 provides
μ L are injected weekly twice.Postoperative 4 weeks, the OA progress of each group mouse is analyzed, standards of grading are：
| Cartilage structure situation | Scoring/point |
| Normal cartilage | 0 |
| Cartilage is normal, but cartilage dyeing weakens | 0.5 |
| Articular surface is smooth, has a small amount of fiber to cover | 1 |
| Articular cartilage shallow-layer fibr tissue covers, and visible thin layer cartilage strips off | 2 |
| Cartilage layers mild wear (20% full-thickness cartilages of <) | 3 |
| Cartilage layers moderate wears (20%-80% full-thickness cartilages) | 5 |
| Cartilage layers severe wears (80% full-thickness cartilages of >) | 6 |
It scores each group mouse, as a result as shown in table 1 below：
1 medial meniscus buckling form mouse therapeutic effect of table
It can be seen from the results above that the rapamycin sustained-release dosage type that 1-6 of the embodiment of the present invention is provided, passes through slow-release material
Slow-release controlled-release is carried out to rapamycin, on the basis of capable of injecting primary at every 4 weeks, effective alleviation and treatment bone is maintained to close
Save scorching effect.Not only curative effect is better than the prior art that comparative example 1 provides, and is administered once and longer treatment is just maintained to imitate
Fruit, weekly administration compared with the prior art twice, can reduce the cost of multiple dosing, reduce the feeling of pain and thorn of patient
Swash property, reduces the adverse reaction brought due to organic solvent and safety accident.
Figure 1A -1D and Fig. 2A and Fig. 2 B show the rapamycin sustained-release dosage type that the 10 μ L embodiment of the present invention 1 of injection provide
To mouse knee joint, OA progress was analyzed in 4 weeks after surgery respectively, 8 weeks.OARSI scorings have significant difference (p=
0.002, p=0.007).By safranin O-Fast Green stain, dye blue is nucleus, and dye red is that growth plate is soft
Bone and articular cartilage, dye green is bone, subchondral bone and its hetero-organization.It can be seen from the figure that the application present invention is real
The process of OA can effectively be alleviated by applying the treatment group of the rapamycin sustained-release dosage type of the offer of example 1, achieve the purpose that treat OA.
Experimental example 2C57 mouse ACLT model experiments
For experiment packet with experimental example 1, concrete operations are as follows：
The C57 mouse big to 8-10 week old is injected intraperitoneally using 10% chloraldurate and carries out anaesthetic treatment, sterilizes knee joint
Neighbouring skin, experimental side knee joint are cut on the outside of kneecap, are successively detached muscle and subcutaneous tissue, are appeared the nearly shin of anterior cruciate ligament
Bone point.It then by 90 degree of knee sprung, is cut in middle-end after anterior cruciate ligament is hooked, avoids injuring meniscus and rear intersection
Ligament, carrying out drawer experiment confirms Anterior Cruciate Ligament Ruptures, then hemostasis and with normal saline flushing wound, layer-by-layer suture joint
Capsule and skin intersect torrid zone cut-out (ACLT) model before building mouse.Control sides using same method appear anterior cruciate ligament but
It does not cut off, postoperative daily check wound, periodically giving penicillin intramuscular injection prevents from infecting, and knee joint is maintained at just without fixation
Under normal feeding environment, animal can be voluntarily movable, ad lib drinking-water.
In addition to control group 1 and model group 2, corresponding rapamycin formulation is injected to experiment each group mouse respectively.Wherein, real
Applying the rapamycin sustained-release dosage type that a 1-6 is provided, 10 μ L, injection in every 4 weeks are primary every time；The injection every time 10 that comparative example 1 provides
μ L are injected weekly twice.Postoperative 4 weeks, the OA progress of each group mouse is analyzed, standards of grading are the same as experimental example 1.
It scores each group mouse, as a result as shown in table 2 below：
Intersect cut-out model mice therapeutic effect in the torrid zone before table 2
| Group | 4w scorings/point | 8w scorings/point | 12w scorings/point |
| Control group 1 | 0 | 0 | 0 |
| Model group 2 | 2.8 | 3.2 | 5.1 |
| Embodiment 1 | 1.2 | 1.9 | 2.2 |
| Embodiment 2 | 1.1 | 2.0 | 2.2 |
| Embodiment 3 | 1.3 | 2.1 | 2.3 |
| Embodiment 4 | 1.3 | 2.2 | 2.4 |
| Embodiment 5 | 1.1 | 2.1 | 2.4 |
| Embodiment 6 | 1.3 | 2.2 | 2.5 |
| Comparative example 1 | 1.5 | 2.4 | 3.0 |
It can be seen from the results above that the rapamycin sustained-release dosage type that 1-6 of the embodiment of the present invention is provided, passes through slow-release material
Slow-release controlled-release is carried out to rapamycin, on the basis of capable of injecting primary at every 4 weeks, effective alleviation and treatment bone is maintained to close
Save scorching effect.Not only curative effect is better than the prior art that comparative example 1 provides, and is administered once and longer treatment is just maintained to imitate
Fruit, weekly administration compared with the prior art twice, can reduce the cost of multiple dosing, reduce the feeling of pain and thorn of patient
Swash property, reduces the adverse reaction brought due to organic solvent and safety accident.
Show that the rapamycin sustained-release dosage type that the 10 μ L embodiment of the present invention 1 of injection provide arrives in Fig. 3 A-3F and Fig. 4 A-4C
Mouse knee joint, OA progress is analyzed in 4 weeks after surgery, 8 weeks and 12 weeks respectively.OARSI scorings have significant difference (p=
0.001, p=0.001 and p=0.0023).By safranin O-Fast Green stain, dye blue is nucleus, dyes red
It is growth plate cartilage and articular cartilage, dye green is bone, subchondral bone and its hetero-organization.Using the embodiment of the present invention 1
The process of OA can effectively be alleviated in the treatment group of the rapamycin sustained-release dosage type of offer, achieve the purpose that treat OA.
Finally it should be noted that：The above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Present invention has been described in detail with reference to the aforementioned embodiments for pipe, it will be understood by those of ordinary skill in the art that：Its according to
So can with technical scheme described in the above embodiments is modified, either to which part or all technical features into
Row equivalent replacement；And these modifications or replacements, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The range of scheme.
Claims (10)
1. a kind of rapamycin sustained-release dosage type, which is characterized in that the rapamycin sustained-release dosage type includes：Rapamycin and sustained release
Material；
Wherein, the mass ratio of the rapamycin and the slow-release material is 1:10-50.
2. rapamycin sustained-release dosage type according to claim 1, which is characterized in that the rapamycin further includes that thunder pa is mould
Plain derivative and forms of rapamycin analogs.
3. rapamycin sustained-release dosage type according to claim 1, which is characterized in that the slow-release material includes macromolecular sustained
Release material and small molecule slow-release material；
Preferably, the polymeric alloy membrane is selected from sodium alginate, chitosan, Poly(D,L-lactide-co-glycolide, gathers in oneself
Ester, polylactic acid, polytrimethylene carbonate, polyglycolic acid, poly butyric ester, polyhydroxybutyrate hydroxyl pentanoate copolymer,
It is one or more in polyorthoester and polyanhydride；
Preferably, the small molecule slow-release material includes lipoid substance, preferably lipoid, and more preferably phosphatide and/or class are solid
Alcohol；
Preferably, the weight average molecular weight of the polymeric alloy membrane is 10000-100000 dalton, preferably 10000-
80000 dalton, more preferably 10000-50000 dalton.
4. rapamycin sustained-release dosage type according to claim 1, which is characterized in that further include emulsifier, it is preferably hydrophilic
Property emulsifier；
Preferably, the emulsifier be selected from polyvinyl alcohol, Tween 80, PEG-100 stearates, stearine, arachidic alcohol,
It is one or more in fatty alcohol polyoxyethylene ether, Compritol 888 ATO or cetearyl glucoside.
5. the preparation method of rapamycin sustained-release dosage type according to any one of claims 1-4, which is characterized in that the preparation
Method includes：
The organic solution for providing the rapamycin and slow-release material of formula ratio, is uniformly mixed with emulsifier, after removing organic solvent,
Obtain the rapamycin sustained-release dosage type.
6. preparation method according to claim 5, which is characterized in that the boiling point of the organic solvent is not higher than 50 DEG C；
Preferably, the organic solvent is selected from acetone, chloroform, methylamine, dimethylamine, ether, pentane, dichloromethane or carbon disulfide
In it is one or more.
7. preparation method according to claim 5, which is characterized in that the organic solution is per 10-30mg slow-release materials
It dissolves and obtains in 0.1-2mL organic solvents with 0.1-2mg rapamycins；
Preferably, it is mixed with 1-10mL emulsifiers per 0.1-2mL organic solvents；
Preferably, the slow-release material is poly lactic-co-glycolic acid, and the organic solvent is dichloromethane, and the emulsifier is
1% (w/v) polyvinyl alcohol.
8. a kind of rapamycin is slow-release injected, which is characterized in that slow including claim 1-4 any one of them rapamycins
Release dosage form or the rapamycin sustained-release dosage type for applying claim 5-7 any one of them preparation methods to be prepared and solvent.
9. rapamycin sustained-release dosage type according to any one of claims 1-4 applies claim 5-7 any one of them
Rapamycin sustained-release dosage type or rapamycin according to any one of claims 8 that preparation method is prepared are slow-release injected to be inhibited
Application in mTORC1.
10. rapamycin sustained-release dosage type according to any one of claims 1-4 applies claim 5-7 any one of them
Rapamycin sustained-release dosage type or rapamycin according to any one of claims 8 that preparation method is prepared are slow-release injected to be controlled in preparation
Treat the application in the drug of osteoarthritis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810754778.XA CN108771656A (en) | 2018-07-10 | 2018-07-10 | Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810754778.XA CN108771656A (en) | 2018-07-10 | 2018-07-10 | Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108771656A true CN108771656A (en) | 2018-11-09 |
Family
ID=64029969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810754778.XA Pending CN108771656A (en) | 2018-07-10 | 2018-07-10 | Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108771656A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109431997A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin locally injecting preparation and preparation method thereof |
| CN114376994A (en) * | 2022-03-04 | 2022-04-22 | 河北工程大学附属医院 | Rapamycin sustained-release medicinal film and preparation method thereof |
| CN115957383A (en) * | 2021-10-12 | 2023-04-14 | 凯诺威医疗科技(武汉)有限公司 | Interventional medical instrument |
| CN116898824A (en) * | 2023-09-14 | 2023-10-20 | 南方医科大学第三附属医院（广东省骨科研究院） | Histamine H1 receptor antagonist slow-release nanoparticle, preparation method thereof, injection and application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634046A (en) * | 2004-10-29 | 2005-07-06 | 山东省眼科研究所 | Use of rapamycin in preparation of intraocularly embedded drug |
| CN102178649A (en) * | 2011-05-05 | 2011-09-14 | 张振华 | Rapamycin liposome eye drops and preparation method thereof |
| CN106110390A (en) * | 2016-06-30 | 2016-11-16 | 丁坦 | A kind of RAPA PLGA support |
| US20170000742A1 (en) * | 2004-12-21 | 2017-01-05 | Board of Regents of the University of Nebraska by and Behalf of the University of Nebraska Medical C | Sustained-release nanoparticle compositions and methods for using the same |
-
2018
- 2018-07-10 CN CN201810754778.XA patent/CN108771656A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634046A (en) * | 2004-10-29 | 2005-07-06 | 山东省眼科研究所 | Use of rapamycin in preparation of intraocularly embedded drug |
| US20170000742A1 (en) * | 2004-12-21 | 2017-01-05 | Board of Regents of the University of Nebraska by and Behalf of the University of Nebraska Medical C | Sustained-release nanoparticle compositions and methods for using the same |
| CN102178649A (en) * | 2011-05-05 | 2011-09-14 | 张振华 | Rapamycin liposome eye drops and preparation method thereof |
| CN106110390A (en) * | 2016-06-30 | 2016-11-16 | 丁坦 | A kind of RAPA PLGA support |
Non-Patent Citations (1)
| Title |
|---|
| 王浩 等: ""雷帕霉素调控自噬在骨关节炎软骨细胞退变中的机制研究"", 《中华骨与关节外科杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109431997A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin locally injecting preparation and preparation method thereof |
| CN115957383A (en) * | 2021-10-12 | 2023-04-14 | 凯诺威医疗科技(武汉)有限公司 | Interventional medical instrument |
| CN114376994A (en) * | 2022-03-04 | 2022-04-22 | 河北工程大学附属医院 | Rapamycin sustained-release medicinal film and preparation method thereof |
| CN116898824A (en) * | 2023-09-14 | 2023-10-20 | 南方医科大学第三附属医院（广东省骨科研究院） | Histamine H1 receptor antagonist slow-release nanoparticle, preparation method thereof, injection and application |
| CN116898824B (en) * | 2023-09-14 | 2024-01-23 | 南方医科大学第三附属医院（广东省骨科研究院） | Histamine H1 receptor antagonist slow-release nanoparticle, preparation method thereof, injection and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6857214B2 (en) | Sustained release composition for injection and its use for treating joint inflammation and associated pain | |
| CN108771656A (en) | Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application | |
| CN103140226B (en) | Preparation for treatment of spinal cord injury | |
| CN104427976B (en) | Hydrophobic depot formulations of active ingredient and preparation method thereof | |
| Yang et al. | Application of liposome-encapsulated hydroxycamptothecin in the prevention of epidural scar formation in New Zealand white rabbits | |
| US8586092B2 (en) | Fulvestrant nanosphere/microsphere and preparative method and use thereof | |
| KR20070057767A (en) | Phospholipid compositions and methods for their preparation and use | |
| JP2000511941A (en) | Long-acting anesthesia in the joint space and body space | |
| JP2009161543A (en) | Composition comprising anti-microtubule agent and polypeptide or polysaccharide, and use thereof for preparation of medicament for treatment of inflammatory condition | |
| US20100203163A1 (en) | Injectable polymer-lipid blend for localized drug delivery | |
| EP2910242B1 (en) | Durable analgetic sebacoyl dinalbuphine ester-plga controlled release formulation | |
| CN108685927A (en) | Include the medical composition and its use of methylenum careuleum class compound and bioactive ingredients | |
| CN104427987A (en) | Formulations and methods for delaying onset of chronic neuropathic pain | |
| Ameena et al. | Cytocompatibility and wound healing activity of chitosan thiocolchicoside lauric acid nanogel in human gingival fibroblast cells | |
| CN108685926A (en) | Include the medical composition and its use of chemical ablation agent and bioactivity glycosides | |
| WO2021137224A1 (en) | Cannabidiolic acid esters for treating muscular dystrophy | |
| CN108785246A (en) | Melbine sustained-release dosage type and preparation method and injection and application | |
| CN116898824B (en) | Histamine H1 receptor antagonist slow-release nanoparticle, preparation method thereof, injection and application | |
| CN106924174A (en) | A kind of joint cavity injection Apremilast gel and preparation method thereof | |
| CN115252621B (en) | Application of small molecular compound in preparation of medicine for treating osteoarthritis | |
| CN111012734A (en) | Drug-loaded reticular in-situ phase-change gel sustained-release system and preparation method thereof | |
| CN112451475B (en) | Long-acting sustained-release gel for treating cavernous pulmonary tuberculosis | |
| WO2024089046A1 (en) | Dosage form for intra-articular injection comprising colchicine and an anesthesic agent in the treatment of crystal-and non-crystal associated acute inflammatory arthritis | |
| US20220339100A1 (en) | Thermosensitive modified chitin hydrogel local anesthetic-loaded sustained-release analgesia system, preparation method and use | |
| EP2244693B1 (en) | Agent for intra-articular injection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181109 |
|
| RJ01 | Rejection of invention patent application after publication |