CN106667897A - Biodegradable slow/controlled-release drug delivery system and preparation method thereof - Google Patents
Biodegradable slow/controlled-release drug delivery system and preparation method thereof Download PDFInfo
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- CN106667897A CN106667897A CN201710084574.5A CN201710084574A CN106667897A CN 106667897 A CN106667897 A CN 106667897A CN 201710084574 A CN201710084574 A CN 201710084574A CN 106667897 A CN106667897 A CN 106667897A
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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- 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
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Abstract
The invention relates to the fields of chemical and medical biological materials and biomedicine, and particularly relates to a biodegradable slow/controlled-release drug delivery system and a preparation method thereof. The system using one or more than two biodegradable three-dimensional network polymers or biodegradable crosslinked elastomers as a drug carrier, and the drug content in the system by weight is more than 0-50%.By using the biodegradable three-dimensional network polymers as the drug carrier, the drug is loaded on the drug carrier through a swelling method. The process provided by the invention is simple and easy to operate; and the drug loading capacity of the drug delivery system can be changed by changing the concentration of a drug solution, the physical behavior of a drug carrier product, dimension parameters and the other parameters. The system has higher application prospects in the fields of tissue engineering and drug slow release, and can be used for disease prevention and treatment and other aspects through surgical sutures, anti-adhesive membranes, tissue engineering scaffolds, subcutaneous implants, contraceptive implants and transdermal or inhalation drug delivery.
Description
Technical field
The present invention relates to chemistry, biomaterial for medical purpose and biologic pharmacological science field, specifically a kind of biodegradation
Type slowly released and controlled-drug delivery system and preparation method thereof.
Background technology
Drug controlled release is conducive to improving curative effect of medication, reduces toxic and side effects, can mitigate the pain of the multiple medication of patient,
Be significant for clinical application level is improved, be research in international coverage in recent years most popular field it
One.For a long time, it is always in drug controlled release field based on the pharmaceutical carrier of macromolecular material and studies for enlivening the most
Individual system.The eighties in 20th century, Segal etc. are occurred in earliest with silicone rubber work using macromolecule as the delivery systme of pharmaceutical carrier
For carrier material, Progesterone is mounted in silicone rubber microcapsule for family planning research.Result of study shows that medicine is when longer
Interior slow release, therapeutic effect is satisfactory.But problem is it is found that organosilicon material can induce after long-term use
Canceration, thus the safety to this kind of material proposes objection.Meanwhile, because of its non-degradable characteristic, silicone rubber can not drop in vivo
Solve as micromolecular compound and be absorbed by organisms or metabolism, place and need second operation to take out after exhaustion of effect.But due to taking
Go out operation more than implant surgery difficulty, not only increased use cost, bring unnecessary pain, Er Qienan to user
Can take out on schedule in all user of guarantee.
In order to overcome disadvantages mentioned above, scientific research personnel is devoted to studying always biodegradable polymer, and expect with
This eliminates the inconvenience that second operation is brought as drug carrier material.Since the eighties in 20th century, although have tens kinds to gather
Compound is proposed as degradable biological material, but so far only a few is approved by the FDA in the United States human implantable,
Such as:PTMC, polycaprolactone, PGA, polylactide and its copolymer etc., in the medicine sustained and controlled release side of putting
Face obtains Preliminary Applications.Although these biodegradable linear polyesters can be with degradation in vivo as micromolecular compound and by body
Absorb, it is to avoid the trouble that second operation takes out, but the problem that generally existing structure is not sufficiently stable so that medicine-carried system carrying drug ratio
Low, poor controllability, before medicine is not discharged completely, it is impossible to keep good mechanical property and collapse, cause medicine
Thing " burst release ", is precisely controlled release and also has very big gap apart from medicine, and to user great side effect even life is brought
Danger, hinders or limits their applications in medicine sustained and controlled release field.Therefore, the continuous renewal with clinical demand and base
In these biodegradable linear polyesters functional material biomedicine field continuous application and expansion, exploitation one class knot
Structure is more stable, the adjustable new slow controlled-release material of degradation time is imperative.Biodegradation three-dimensional network polymer or life
Thing degradation-type cross-linked elastomer has stable three-dimensional net structure, excellent pliability, elasticity and other line styles such as modulus can
The mechanical performance that degraded medical macromolecular materials are lacked, it is ensured that pharmaceutical carrier generates space in degradation process, forms
The spongy space structure of class, and after occurring largely to degrade, remains to keep original three dimensional structure and good
Mechanical performance, the slow controlled release for medicine provides strong guarantee.
Chinese invention patent application (publication number:The A of CN 102989044), there is provided a kind of biodegradable medical high polymer
Tubing and preparation method thereof, when polymerization forming method prepares biodegradable cross-linked polymer pipe in using mould, can exist simultaneously
Medicine is introduced directly in polymer process, the biodegradable polymers tubing of pastille is obtained.It is disadvantageous in that, directly
Introducing medicine can only be free from the medicine of oh group or without the medicine that can participate in polyreaction group, once medicine
Group take part in polyreaction, drug inactivation will be caused, and then cause therapeutic effect to reduce, or even life is brought to user
It is dangerous.
Chinese invention patent application (publication number:The A of CN 102743329, CN 102743328 A) a kind of new palace is provided
A kind of interior slowly released and controlled-drug delivery system and preparation method thereof and biodegradation material in utero slowly released and controlled-drug delivery system and preparation method thereof,
It is that medicine is mixed homogeneously with linear polymer or star-type polymer when the two prepares biodegradation cross linked polymer medicated core,
Made compound using screw extruder method or die pressing is carried out crosslinking and is prepared after medicated core using irradiation method.Its deficiency
Place is that cross-linking radiation can equally destroy the chemical constitution of drug molecule, and then cause drug inactivation, and then cause therapeutic effect
Reduce, or even life danger is brought to user.
The content of the invention
For above-mentioned technical problem present in prior art, it is an object of the invention to provide a kind of Biodegradable is slow
Controlled-release administrating system and preparation method thereof, can effectively eliminate because pharmaceutical group participates in polyreaction or cross-linking radiation destruction medicine
Thing molecular structure and cause the negative effect and potential hazard that drug inactivation brought.
In order to solve above-mentioned technical problem, the technical scheme is that:
A kind of Biodegradable slowly released and controlled-drug delivery system, the system is with one or more Biodegradable three-dimensional networks
Polymer or Biodegradable cross-linked elastomer are pharmaceutical carrier, and the drug weight content in system is more than 0 to 50%.
Described Biodegradable slowly released and controlled-drug delivery system, the drug weight preferred content in system is 10~20%.
Described Biodegradable slowly released and controlled-drug delivery system, medicine is hormone medicine, anti-inflammatory analgetic class medicine, antiallergic
Class medicine, antifertility class medicine, antitumor class medicine, anti-senile dementia class medicine, anti-schizophrenia class medicine, classes of anti-infective medicine
Thing, immunomodulating class medicine, antiproliferative pharmaceutical, neuroleptic and neurasthenia treating class medicine or polypeptide protein and vaccine
Bio-pharmaceutical.
Described Biodegradable slowly released and controlled-drug delivery system, pharmaceutical carrier article shape variation, using wire, it is bar-shaped,
Tubulose, lamellar, membranaceous, graininess, powder, weaving object, solid or irregularly shaped body.
Described Biodegradable slowly released and controlled-drug delivery system, Biodegradable three-dimensional network polymer is Acetic acid, hydroxy-, bimol. cyclic ester, L- third
Lactide, DL- lactides, beta-propiolactone, (R, S)-Alpha-Methyl -- propiolactone, 3- methyl-ss-propiolactones, β-benzyloxycarbonyl group-β-the third
Lactone, beta-butyrolactone, gamma-butyrolacton, α-bromo- gamma-butyrolacton, alpha-methylene-gamma-butyrolactone, (R) -3- hydroxyl-γ-Ding Nei
Ester, (R)-(-) -4- methylol butyrolactone, (S)-(+) -4- methylol butyrolactone, (S)-(-)-Alpha-hydroxy-gamma-butyrolacton,
(S) -3- hydroxy-gamma-butyrolactones, DL- Alpha-hydroxies-beta, beta-dimethyl-gamma-butyrolacton, δ-valerolactone, Beta-methyl-δ-valerolactone,
(R) -4- methyl-δ-valerolactone, DL- Beta-methyls-beta-hydroxy-δ-valerolactone, (R) -5- methyl-δ-valerolactone, gamma-valerolactone,
6-caprolactone, δ-caprolactone, γ-hexalactone, 5- hydroxyl caprolactones, 3- methyl -4- oxo -6- caprolactones, 3- methyl-ε-oneself in
Ester, 4- methyl-epsilon-caprolactones, 4- ethyl-s-caprolactones, 4- propyl group -6-caprolactone, 5- methyl-epsilon-caprolactones, 6- methyl-ε -
Caprolactone, γ-heptalactone, 7- methyl heptalactones;γ-octalactone, δ-octalactone, 8- methyl caprylolactones, 4- hydroxy-3-methyls-
Caprylolactone, 1,4- caprylolactones, nonyl lactone, δ-nonalactone, γ-decalactone, δ-decalactone, ε-decalactone, 4- hydroxyls 11
Acid-gamma lactone, δ-dodecalactone, γ-dodecalactone, 12- methyl-dodecalactone, in 2- methylene -4- oxos -12- 12
Ester, trimethylene carbonate, 5- benzyloxy trimethylene carbonates, 5- benzyloxycarbonyl group trimethylene carbonates, 5- allyloxys
Trimethylene carbonate, 5- methyl -5- benzyloxycarbonyl group trimethylene carbonates, 5- ethyl -5- methylol trimethylene carbonates,
5- ethyl -5- phenyl trimethylene carbonates, 5- ethyl -5- butyl trimethylene carbonates, 2,2- dimethyltrimethylene carbon
The propargyl oxygen carbonyl trimethylene carbonate of acid esters, 2- ethoxycarbonyl-2-methyl trimethylene carbonates, 2- methyl -2-, 2- first
Base -2- allyloxycarbonyl trimethylene carbonates, 2- methyl -2- Cortex Cinnamomi acyl-oxygen methyl trimethylene carbonates, 2- ethyl -2- meat
Osmanthus acyloxymethyl trimethylene carbonate, 2,4- dioxo spiros [5.5] hendecane -3- ketone, 1- vinyl -2,4- dioxo spiros
[5.5] hendecane -3- ketone, 1,3- dioxolan-2-ones, 1,4- dioxane-2-ketones, 5- benzyloxymethyl -1,4- dioxane -
2- ketone, 1,5- Dioxepane -2- ketone, caprolactam, N- acetyl caprolactams, N- caprolactams, DL- amino oneself
Lactams, 3- inferior pentenyl -4- butyrolactams, N- bromine caprolactams, N- methyl caprolactam, oenantholcatam, (±)-α-ammonia
Base-epsilon-caprolactams, morpholine -2,5- diketone, 3- methyl morpholine -2,5- diketone, 3- (benzyloxycarbonyl group ethyl)-morpholine -2,5- bis-
Ketone, (3S) -3- (benzyloxycarbonyl-methyl) morpholine -2,5- diketone, (3S, 6RS) -3- (benzyloxycarbonyl-methyl) -6- Methyl-morpholines -
2,5- diketone, (3s, 6RS) -3- [4- (benzyloxycarbonyl amino) butyl] -6- Methyl-morpholine -2,5- diketone, (3S, 6RS) -3- couple
Thio methylol -6- Methyl-morpholines -2,5- the diketone of methoxybenzyl, 3-N- benzyloxycarbonyl groups lysyl--morpholine -2,5- diketone, 6-
Isopropyl-morpholine -2,5- diketone, 6- isopropyl -3- Methyl-morpholine -2,5- diketone, maleic anhydride, succinic anhydride, methyl fourth two
Anhydride, 2- methylene-succinic anhydride, tetrafluoro succinic anhydride, glutaric anhydride, 3,3- tetramethyleneglutaric acid acid anhydrides, 3,3- dimethyl
Glutaric anhydride, 2,2- dimethylated pentanedioic acid acid anhydrides, 3- ethyl -3- methylglutaric acid acid anhydrides, hexafluoroglutaric anhydride, adipic anhydride, the last of the ten Heavenly stems two
Anhydride, N- carboxyl-L-Alanine-ring inner-acid anhydrides, 2- methoxyl group -2- oxygen -1,3,2- dioxaphospholane, 2- ethyoxyl -2-
Oxygen -1,3,2- dioxaphospholane, 2- chloroethoxy -2- oxygen -1,3,2- dioxaphospholane, the chloro- 2- oxygen -1,3,2- of 2-
Propargyl epoxide -2- oxygen -1,3,2- the dioxaphospholane of dioxaphospholane, 2-, 5,5- dimethyl -2- oxygen -1,3,2- two
The chloro- 1,3,2- dioxaphosphorinanes -2- ketone of oxygen phospholane, 5,5- dimethyl -2-, ethylidene ethyl phosphonic acid ester EEP, Asia
Ethyl isobutyl base phosphate ester EIBP, ethylidene 1-isobutyl-3,5-dimethylhexylphosphoric acid ELP, ethylidene octadecyl phosphate ester ESP and its derivative
One or more in the cross-linked homopolymer or cross-linked copolymer of thing;
Biodegradable cross-linked elastomer is network polyester, the poly- decanedioic acid glycerol of polynary aromatic acid and polycaprolactone glycol
Ester, poly- citric acid ethohexadiol ester, poly- decanedioic acid-ethylene glycol-glyceride, hydroxy alkanoic acid be modified the acid of poly- hydroxy alkyl, Polyethylene Glycol/
Poly terephthalic acid based block copolymer, polybutylene terephthalate (PBT)-co- polycyclohexylene's diformazan alcohol esters-
B- Polyethylene Glycol, polyether ester amides, poly- peptide, poe, thermoplastic starch-based bioelastomer, thermosetting polyester elastomer,
One or more in thermosetting polyurethane elastomer, thermo-set polyether ester elastomer.
The preparation method of described Biodegradable slowly released and controlled-drug delivery system, is prepared using swelling method, is comprised the steps:
(1) medicine is dissolved in into organic solvent, the controllable drug solution of compound concentration;
(2) pharmaceutical carrier product is placed in drug solution, is sufficiently stirred for, using the swelling character of pharmaceutical carrier by medicine
Solution is absorbed to support material internal;
(3) organic solvent is removed, obtains Biodegradable slowly released and controlled-drug delivery system.
The preparation method of described Biodegradable slowly released and controlled-drug delivery system, gives as needed to the slow controlled release of Biodegradable
Medicine system carries out face coat, and coating composition is Acetic acid, hydroxy-, bimol. cyclic ester, L- lactides, DL- lactides, beta-propiolactone, (R, S)-α-first
Base -- propiolactone, 3- methyl-ss-propiolactones, β-benzyloxycarbonyl group-beta-propiolactone, beta-butyrolactone, gamma-butyrolacton, α-bromo- γ-fourth
Lactone, alpha-methylene-gamma-butyrolactone, (R) -3- hydroxy-gamma-butyrolactones, (R)-(-) -4- methylol butyrolactone, (S)-(+) -
4- methylol butyrolactone, (S)-(-)-Alpha-hydroxy-gamma-butyrolacton, (S) -3- hydroxy-gamma-butyrolactones, DL- Alpha-hydroxy-β, β-two
Methyl-gamma-butyrolactone, δ-valerolactone, Beta-methyl-δ-valerolactone, (R) -4- methyl-δ-valerolactone, DL- Beta-methyl-beta-hydroxies -
δ-valerolactone, (R) -5- methyl-δ-valerolactone, gamma-valerolactone, 6-caprolactone, δ-caprolactone, γ-hexalactone, 5- hydroxyls are in oneself
Ester, 3- methyl -4- oxo -6- caprolactones, 3- methyl-epsilon-caprolactones, 4- methyl-epsilon-caprolactones, 4- ethyl-s-caprolactones, 4-
Propyl group -6-caprolactone, 5- methyl-epsilon-caprolactones, 6- methyl-epsilon-caprolactones, γ-heptalactone, 7- methyl heptalactones;γ-Xin Nei
Ester, δ-octalactone, 8- methyl caprylolactones, 4- hydroxy-3-methyls-caprylolactone, 1,4- caprylolactones, nonyl lactone, δ-nonalactone,
γ-decalactone, δ-decalactone, ε-decalactone, 4- hydroxyls undecanoic acid-gamma lactone, δ-dodecalactone, γ-dodecalactone, 12- first
Base-dodecalactone, 2- methylene -4- oxo -12- dodecalactones, trimethylene carbonate, 5- benzyloxy trimethylene carbonic acid
Ester, 5- benzyloxycarbonyl group trimethylene carbonates, 5- allyloxy trimethylene carbonates, the methylene of 5- methyl -5- benzyloxycarbonyl groups three
Base carbonic ester, 5- ethyl -5- methylol trimethylene carbonates, 5- ethyl -5- phenyl trimethylene carbonates, 5- ethyl -5-
Butyl trimethylene carbonate, 2,2- dimethyltrimethylene carbonates, 2- ethoxycarbonyl-2-methyl trimethylene carbonates,
The propargyl oxygen carbonyl trimethylene carbonates of 2- methyl -2-, 2- methyl -2- allyloxycarbonyl trimethylene carbonates, 2- methyl -2-
Cortex Cinnamomi acyl-oxygen methyl trimethylene carbonate, 2- ethyl -2- Cortex Cinnamomi acyl-oxygen methyl trimethylene carbonates, 2,4- dioxo spiros
[5.5] hendecane -3- ketone, 1- vinyl -2,4- dioxo spiros [5.5] hendecane -3- ketone, 1,3- dioxolan-2-ones, 1,4-
Dioxane-2-ketone, 5- benzyloxymethyl -1,4- dioxane-2-ketones, 1,5- Dioxepane -2- ketone, caprolactam, N-
Acetyl caprolactam, N- caprolactams, DL- aminocaproic lactams, 3- inferior pentenyl -4- butyrolactams, N- bromines are in oneself
Amide, N- methyl caprolactam, oenantholcatam, (±)-alpha-amido-epsilon-caprolactams, morpholine -2,5- diketone, 3- methyl morpholines-
2,5- diketone, 3- (benzyloxycarbonyl group ethyl)-morpholine -2,5- diketone, (3S) -3- (benzyloxycarbonyl-methyl) morpholine -2,5- diketone,
(3S, 6RS) -3- (benzyloxycarbonyl-methyl) -6- Methyl-morpholine -2,5- diketone, (3s, 6RS) -3- [4- (benzyloxycarbonyl amino) fourths
Base] -6- Methyl-morpholine -2,5- diketone, (3S, 6RS) -3- methylol -6- Methyl-morpholine -2,5-s two thio to methoxybenzyl
Ketone, 3-N- benzyloxycarbonyl groups lysyl--morpholine -2,5- diketone, 6- isopropyls-morpholine -2,5- diketone, 6- isopropyl -3- methyl -
Morpholine -2,5- diketone, maleic anhydride, succinic anhydride, dimethyl succinic acid acid anhydride, 2- methylene-succinic anhydride, tetrafluoro succinic anhydride,
Glutaric anhydride, 3,3- tetramethyleneglutaric acid acid anhydrides, 3,3- dimethylated pentanedioic acid acid anhydrides, 2,2- dimethylated pentanedioic acid acid anhydrides, 3- ethyl -3-
Methylglutaric acid acid anhydride, hexafluoroglutaric anhydride, adipic anhydride, sebacic anhydride, N- carboxyl-L-Alanine-ring inner-acid anhydrides, 2- methoxies
Base -2- oxygen -1,3,2- dioxaphospholane, 2- ethyoxyl -2- oxygen -1,3,2- dioxaphospholane, 2- chloroethoxy -2-
The chloro- 2- oxygen -1,3,2- dioxaphospholane of oxygen -1,3,2- dioxaphospholane, 2-, the propargyl epoxide -2- oxygen -1,3,2- of 2-
Dioxaphospholane, 5,5- dimethyl -2- oxygen -1,3,2- dioxaphospholane, the chloro- 1,3,2- bis- of 5,5- dimethyl -2-
Oxygen phospha cyclohexane -2- ketone, ethylidene ethyl phosphonic acid ester EEP, ethylidene isobutyl group phosphate ester EIBP, ethylidene dodecyl phosphorus
Acid esters ELP, the homopolymer of ethylidene octadecyl phosphate ester ESP and its derivant or copolymer one or more, apply
Thickness degree is below 2mm;Or, by Biodegradable slowly released and controlled-drug delivery system loaded in capsule.
The preparation method of described Biodegradable slowly released and controlled-drug delivery system, in step (1), drug solution concentration is controllable,
Drug level is preferably 1~10mg/ml.
The preparation method of described Biodegradable slowly released and controlled-drug delivery system, the shape and size of pharmaceutical carrier are arbitrarily adjusted
Section, drug loading is controllable therewith.
The application of described Biodegradable slowly released and controlled-drug delivery system, the system is used for operation suture thread, Antiadhesive film, group
Weaver's engineering support, subcutaneous implant, contraception implants, transdermal or inhalation.
Advantages of the present invention and beneficial effect are:
1st, Biodegradable slowly released and controlled-drug delivery system of the invention, it is possible to provide the good pharmaceutical carrier of dimensional stability,
After occurring largely to degrade, the original three dimensional structure of holding and good mechanical performance are remained to, be that the slow controlled release of medicine is carried
For strong guarantee, medicine " burst release " effect produced by the degraded of linear carrier can be effectively eliminated.
2nd, Biodegradable slowly released and controlled-drug delivery system of the invention, article shape variation, is suitably applied different demands
Clinical practice.
3rd, Biodegradable slowly released and controlled-drug delivery system of the invention, can be loaded various kinds of drug by the way of swelling load medicine
In pharmaceutical carrier, expansion can use medicament categories;Meanwhile, swelling load medicine can be eliminated effectively because pharmaceutical group participates in polyreaction
Or cross-linking radiation destruction drug molecular structure, and cause the negative effect and potential hazard that drug inactivation brought.
4th, the drug loading of Biodegradable slowly released and controlled-drug delivery system of the invention can be according to clinical needs, by pharmaceutical carrier
Shape, size and Pharmaceutical concentration can adjust arbitrarily.
5th, Biodegradable slowly released and controlled-drug delivery system of the invention, carries prescription formula simple to operate flexibly.
Description of the drawings
Fig. 1 (a)-Fig. 1 (b) is to prepare by pharmaceutical carrier of PTMC three-dimensional network polymer in the present invention
Biodegradable slowly released and controlled-drug delivery system scanning electron microscopic picture.Wherein, Fig. 1 (a) is the surface topography of sample after cleaning;Figure
1 (b) is cross-sectional morphology.
Fig. 2 is the slow controlled release of Biodegradable prepared as pharmaceutical carrier with PTMC three-dimensional network polymer
Gestodene's release profiles of drug-supplying system.
Specific embodiment
The following example is now given so that those skilled in the art are easier to understand and implement the present invention, but they should not be by
It is considered as restriction the scope of the present invention, and is only its example and representative.Relevant research worker is according to foregoing invention content to the present invention
The modifications and adaptations of some point of essence are made, protection scope of the present invention is still fallen within.
Embodiment 1
In the present embodiment, Biodegradable slowly released and controlled-drug delivery system and preparation method thereof is as follows:
Precise 100mg gestodene is dissolved in 50ml chloroforms, and configuration concentration is the drug solution of 2mg/ml;Will be long
Degree 20mm, the PTMC three-dimensional network polymer bar (its weight is 150mg) of diameter 3mm are placed in drug solution
In, take out after 7 days, after placing 1 day naturally, constant weight is dried under vacuum to, obtain the biodegradation that drug loading is 20mg gestodene
Type slowly released and controlled-drug delivery system.
As shown in Fig. 1 (a)-Fig. 1 (b), PTMC three-dimensional network polymer of the present invention is pharmaceutical carrier system
Standby Biodegradable slowly released and controlled-drug delivery system, with following features:After cleaning, system surfaces are without drug-rich and separate out existing
As, the fracture morphology for transshipping medicine implant can be seen that inside it than more loose, medicine crystal can it is dispersed wherein, reach
To good load drug effect fruit.
Embodiment 2
In the present embodiment, Biodegradable slowly released and controlled-drug delivery system and preparation method thereof is as follows:
Precise 100mg gestodene is dissolved in 50ml chloroforms, and configuration concentration is the drug solution of 2mg/ml;Will be long
Degree 30mm, the PTMC three-dimensional network polymer bar (its weight is 225mg) of diameter 3mm are placed in drug solution
In, take out after 7 days, after placing 1 day naturally, constant weight is dried under vacuum to, obtain the biodegradation that drug loading is 30mg gestodene
Type slowly released and controlled-drug delivery system.
Embodiment 3
In the present embodiment, Biodegradable slowly released and controlled-drug delivery system and preparation method thereof is as follows:
Precise 100mg gestodene is dissolved in 50ml chloroforms, and configuration concentration is the drug solution of 2mg/ml;Will be long
Degree 20mm, the PTMC three-dimensional network polymer bar (its weight is 150mg) of diameter 3mm are placed in drug solution
In, take out after 7 days, after placing 1 day naturally, constant weight is dried under vacuum to, surface spraying thickness is 0.5mm polytrimethylene carbonic acid
Ester, drying obtains the Biodegradable slowly released and controlled-drug delivery system that drug loading is 20mg gestodene to constant weight.
Embodiment 4
In the present embodiment, Biodegradable slowly released and controlled-drug delivery system and preparation method thereof is as follows:
Precise 100mg gestodene is dissolved in 50ml chloroforms, and configuration concentration is the drug solution of 2mg/ml;Will be long
Degree 20mm, external diameter 3mm, internal diameter are put for the PTMC three-dimensional network polymer pipe (its weight is 80mg) of 2mm
In drug solution, take out after 7 days, after placing 1 day naturally, be dried under vacuum to constant weight, obtain drug loading for 10mg gestodene
Biodegradable slowly released and controlled-drug delivery system.
Embodiment 5
In the present embodiment, Biodegradable slowly released and controlled-drug delivery system and preparation method thereof is as follows:
Precise 150mg ibuprofen is dissolved in 50ml chloroforms, and configuration concentration is the drug solution of 3mg/ml;By particle diameter
The PTMC three-dimensional network polymer beads and polycaprolactone three-dimensional network for being respectively 50mg for 2mm, weight gather
Polymer beads are placed in drug solution, are taken out after 7 days, after placing 1 day naturally, constant weight are dried under vacuum to, loaded on polycaprolactone glue
It is intracapsular, obtain the Biodegradable slowly released and controlled-drug delivery system that drug loading is 16mg ibuprofen.
Embodiment 6
The Biodegradable slowly released and controlled-drug delivery system that embodiment 1 is obtained is some using deionized water and washes of absolute alcohol
It is secondary, to remove the medicine for being enriched in system surfaces.Dried Biodegradable slowly released and controlled-drug delivery system is soaked in into 20ml to steam
Distilled water, the constant temperature shaking under the conditions of 37 ± 1 DEG C, the frequency that shakes changed a solution per 24 hours for 65 beats/min, used high performance liquid chromatography
Medicament contg in instrument test solution.Pharmaceutical release time 16 days, rate of release is about 120 micro- grams/day, as a result sees Fig. 2.
Figure it is seen that the Biodegradable slowly released and controlled-drug delivery system drug release effect that embodiment 1 is obtained is substantially, can be with
The slow release to gestodene is realized, and later stage release tends to be steady, the performance with good sustained and controlled release medicament.
Embodiment result shows, Biodegradable slowly released and controlled-drug delivery system prepared by the present invention, process is simple, it is easy to grasp
Make, the drug loading of drug-supplying system can pass through the parameters such as shape, size and the liquor strength of change carrier material product and realize.This is
The effect that system is put with good biodegradability, biocompatibility and medicine sustained and controlled release, in organizational project and medicine
Slow release field have higher application prospect, can be used for operation suture thread, Antiadhesive film, tissue engineering bracket, subcutaneous implant,
Contraception implants, transdermal or inhalation disease prevention and treatment etc..
Claims (10)
1. a kind of Biodegradable slowly released and controlled-drug delivery system, it is characterised in that the system is with one or more biodegradations
Type three-dimensional network polymer or Biodegradable cross-linked elastomer are pharmaceutical carrier, and the drug weight content in system is more than 0
To 50%.
2. according to the Biodegradable slowly released and controlled-drug delivery system described in claim 1, it is characterised in that the drug weight in system
Preferred content is 10~20%.
3. according to the Biodegradable slowly released and controlled-drug delivery system described in claim 1, it is characterised in that medicine is amcinonide
It is thing, anti-inflammatory analgetic class medicine, antiallergic class medicine, antifertility class medicine, antitumor class medicine, anti-senile dementia class medicine, anti-
Schizophrenia class medicine, anti-infection drug, immunomodulating class medicine, antiproliferative pharmaceutical, neuroleptic and neurasthenia treating class
Medicine or polypeptide protein and vaccine bio-pharmaceutical.
4. according to the Biodegradable slowly released and controlled-drug delivery system described in claim 1, it is characterised in that pharmaceutical carrier article shape
Variation, using wire, bar-shaped, tubulose, lamellar, membranaceous, graininess, powder, weaving object, solid or irregular shape
Shape body.
5. according to the Biodegradable slowly released and controlled-drug delivery system described in claim 1, it is characterised in that Biodegradable three dimensional network
Network polymer is Acetic acid, hydroxy-, bimol. cyclic ester, L- lactides, DL- lactides, beta-propiolactone, (R, S)-Alpha-Methyl -- propiolactone, 3- methyl-β-the third
Lactone, β-benzyloxycarbonyl group-beta-propiolactone, beta-butyrolactone, gamma-butyrolacton, α-bromo- gamma-butyrolacton, alpha-methylene-γ-Ding Nei
Ester, (R) -3- hydroxy-gamma-butyrolactones, (R)-(-) -4- methylol butyrolactone, (S)-(+) -4- methylol butyrolactone, (S) -
(-)-Alpha-hydroxy-gamma-butyrolacton, (S) -3- hydroxy-gamma-butyrolactones, DL- Alpha-hydroxies-beta, beta-dimethyl-gamma-butyrolacton, δ-penta
Lactone, Beta-methyl-δ-valerolactone, (R) -4- methyl-δ-valerolactone, DL- Beta-methyls-beta-hydroxy-δ-valerolactone, (R) -5- first
Base-δ-valerolactone, gamma-valerolactone, 6-caprolactone, δ-caprolactone, γ-hexalactone, 5- hydroxyl caprolactones, 3- methyl -4- oxos -
6- caprolactones, 3- methyl-epsilon-caprolactones, 4- methyl-epsilon-caprolactones, 4- ethyl-s-caprolactones, 4- propyl group -6-caprolactone, 5- first
Base -6-caprolactone, 6- methyl-epsilon-caprolactones, γ-heptalactone, 7- methyl heptalactones;γ-octalactone, δ-octalactone, 8- methyl
Caprylolactone, 4- hydroxy-3-methyls-caprylolactone, 1,4- caprylolactones, nonyl lactone, δ-nonalactone, γ-decalactone, δ-decalactone,
ε-decalactone, 4- hydroxyls undecanoic acid-gamma lactone, δ-dodecalactone, γ-dodecalactone, 12- methyl-dodecalactone, 2- methylenes
Base -4- oxo -12- dodecalactones, trimethylene carbonate, 5- benzyloxy trimethylene carbonates, the methylene of 5- benzyloxycarbonyl groups three
Base carbonic ester, 5- allyloxy trimethylene carbonates, 5- methyl -5- benzyloxycarbonyl group trimethylene carbonates, 5- ethyl -5- hydroxyls
Methyl trimethylene carbonate, 5- ethyl -5- phenyl trimethylene carbonates, 5- ethyl -5- butyl trimethylene carbonates, 2,
The propargyl oxygen carbonyl three of 2- dimethyltrimethylene carbonates, 2- ethoxycarbonyl-2-methyl trimethylene carbonates, 2- methyl -2-
Carbonate, 2- methyl -2- allyloxycarbonyl trimethylene carbonates, 2- methyl -2- Cortex Cinnamomi acyl-oxygen methyl trimethylenes
Carbonic ester, 2- ethyl -2- Cortex Cinnamomi acyl-oxygen methyl trimethylene carbonates, 2,4- dioxo spiros [5.5] hendecane -3- ketone, 1- second
Thiazolinyl -2,4- dioxo spiros [5.5] hendecane -3- ketone, 1,3- dioxolan-2-ones, 1,4- dioxane-2-ketones, 5- benzyloxies
Methyl isophthalic acid, 4- dioxane-2-ketones, 1,5- Dioxepane -2- ketone, caprolactam, N- acetyl caprolactams, N- vinyls
Caprolactam, DL- aminocaproic lactams, 3- inferior pentenyl -4- butyrolactams, N- bromine caprolactams, N- methyl caprolactam, heptan
Lactams, (±)-alpha-amido-epsilon-caprolactams, morpholine -2,5- diketone, 3- methyl morpholine -2,5- diketone, 3- (benzyloxycarbonyl group second
Base)-morpholine -2,5- diketone, (3S) -3- (benzyloxycarbonyl-methyl) morpholine -2,5- diketone, (3S, 6RS) -3- (benzyloxycarbonyl group first
Base) -6- Methyl-morpholine -2,5- diketone, (3s, 6RS) -3- [4- (benzyloxycarbonyl amino) butyl] -6- Methyl-morpholines -2,5- two
Ketone, (3S, 6RS) -3- methylol -6- Methyl-morpholines -2,5- diketone thio to methoxybenzyl, 3-N- benzyloxycarbonyl group lysyl-s -
Morpholine -2,5- diketone, 6- isopropyls-morpholine -2,5- diketone, 6- isopropyl -3- Methyl-morpholine -2,5- diketone, maleic anhydride,
Succinic anhydride, dimethyl succinic acid acid anhydride, 2- methylene-succinic anhydride, tetrafluoro succinic anhydride, glutaric anhydride, 3,3- tetramethylenes penta
Dicarboxylic anhydride, 3,3- dimethylated pentanedioic acid acid anhydrides, 2,2- dimethylated pentanedioic acid acid anhydrides, 3- ethyl -3- methylglutaric acid acid anhydrides, hexafluoro 1,3-propanedicarboxylic acid
Acid anhydride, adipic anhydride, sebacic anhydride, N- carboxyl-L-Alanine-ring inner-acid anhydrides, 2- methoxyl group -2- oxygen -1,3,2- dioxy phosphorus heterocycles
Pentane, 2- ethyoxyl -2- oxygen -1,3,2- dioxaphospholane, 2- chloroethoxy -2- oxygen -1,3,2- dioxaphospholane,
The chloro- 2- oxygen -1,3,2- dioxaphospholane of 2-, the propargyl epoxide -2- oxygen -1,3,2- dioxaphospholane of 2-, 5,5- diformazans
Base -2- oxygen -1,3,2- dioxaphospholane, the chloro- 1,3,2- dioxaphosphorinanes -2- ketone of 5,5- dimethyl -2-, ethylidene
Ethyl phosphonic acid ester EEP, ethylidene isobutyl group phosphate ester EIBP, ethylidene 1-isobutyl-3,5-dimethylhexylphosphoric acid ELP, ethylidene octadecyl phosphorus
One or more in the cross-linked homopolymer or cross-linked copolymer of acid esters ESP and its derivant;
Biodegradable cross-linked elastomer be the network polyester of polynary aromatic acid and polycaprolactone glycol, poly- decanedioic acid glyceride,
Poly- citric acid ethohexadiol ester, poly- decanedioic acid-ethylene glycol-glyceride, hydroxy alkanoic acid are modified the acid of poly- hydroxy alkyl, Polyethylene Glycol/poly-
Terephthaldehyde's acrylic block copolymers, polybutylene terephthalate (PBT)-co- polycyclohexylene diformazan alcohol ester-b-
Polyethylene Glycol, polyether ester amides, poly- peptide, poe, thermoplastic starch-based bioelastomer, thermosetting polyester elastomer, heat
One or more in curable polyurethane elastomer, thermo-set polyether ester elastomer.
6. the preparation method of the Biodegradable slowly released and controlled-drug delivery system described in a kind of claim 1, it is characterised in that using molten
Prepared by swollen method, comprise the steps:
(1) medicine is dissolved in into organic solvent, the controllable drug solution of compound concentration;
(2) pharmaceutical carrier product is placed in drug solution, is sufficiently stirred for, using the swelling character of pharmaceutical carrier by drug solution
Absorb to support material internal;
(3) organic solvent is removed, obtains Biodegradable slowly released and controlled-drug delivery system.
7. according to the preparation method of the Biodegradable slowly released and controlled-drug delivery system described in claim 6, it is characterised in that according to need
To carry out face coat to Biodegradable slowly released and controlled-drug delivery system, coating composition be Acetic acid, hydroxy-, bimol. cyclic ester, L- lactides, DL- lactides,
Beta-propiolactone, (R, S)-Alpha-Methyl -- propiolactone, 3- methyl-ss-propiolactones, β-benzyloxycarbonyl group-beta-propiolactone, beta-butyrolactone,
Gamma-butyrolacton, α-bromo- gamma-butyrolacton, alpha-methylene-gamma-butyrolactone, (R) -3- hydroxy-gamma-butyrolactones, (R)-(-) -4- hydroxyls
Methylbutyrolactone, (S)-(+) -4- methylol butyrolactone, (S)-(-)-Alpha-hydroxy-gamma-butyrolacton, (S) -3- hydroxyl-γ-Ding Nei
In ester, DL- Alpha-hydroxies-beta, beta-dimethyl-gamma-butyrolacton, δ-valerolactone, Beta-methyl-δ-valerolactone, (R) -4- methyl-δ-penta
Ester, DL- Beta-methyls-beta-hydroxy-δ-valerolactone, (R) -5- methyl-δ-valerolactone, gamma-valerolactone, 6-caprolactone, δ-caprolactone,
γ-hexalactone, 5- hydroxyl caprolactones, 3- methyl -4- oxo -6- caprolactones, 3- methyl-epsilon-caprolactones, 4- methyl-ε-oneself in
Ester, 4- ethyl-s-caprolactones, 4- propyl group -6-caprolactone, 5- methyl-epsilon-caprolactones, 6- methyl-epsilon-caprolactones, γ-heptalactone,
7- methyl heptalactones;γ-octalactone, δ-octalactone, 8- methyl caprylolactones, 4- hydroxy-3-methyls-caprylolactone, 1,4- caprylolactones,
In nonyl lactone, δ-nonalactone, γ-decalactone, δ-decalactone, ε-decalactone, 4- hydroxyls undecanoic acid-gamma lactone, δ-ten two
Ester, γ-dodecalactone, 12- methyl-dodecalactone, 2- methylene -4- oxo -12- dodecalactones, trimethylene carbonate, 5-
Benzyloxy trimethylene carbonate, 5- benzyloxycarbonyl group trimethylene carbonates, 5- allyloxy trimethylene carbonates, 5- first
Base -5- benzyloxycarbonyl group trimethylene carbonates, 5- ethyl -5- methylol trimethylene carbonates, the methylene of 5- ethyl -5- phenyl three
Base carbonic ester, 5- ethyl -5- butyl trimethylene carbonates, 2,2- dimethyltrimethylene carbonates, 2- carbethoxyl group -2- first
The propargyl oxygen carbonyl trimethylene carbonate of base trimethylene carbonate, 2- methyl -2-, the methylene of 2- methyl -2- allyloxycarbonyls three
Base carbonic ester, 2- methyl -2- Cortex Cinnamomi acyl-oxygen methyl trimethylene carbonates, 2- ethyl -2- Cortex Cinnamomi acyl-oxygen methyl trimethylene carbon
Acid esters, 2,4- dioxo spiros [5.5] hendecane -3- ketone, 1- vinyl -2,4- dioxo spiros [5.5] hendecane -3- ketone, 1,3-
Dioxolan-2-one, 1,4- dioxane-2-ketones, 5- benzyloxymethyl -1,4- dioxane-2-ketones, 1,5- dioxa cycloheptyls
Alkane -2- ketone, caprolactam, N- acetyl caprolactams, N- caprolactams, DL- aminocaproic lactams, 3- inferior pentenyls -
4- butyrolactams, N- bromine caprolactams, N- methyl caprolactam, oenantholcatam, (±)-alpha-amido-epsilon-caprolactams, morpholine-
2,5- diketone, 3- methyl morpholine -2,5- diketone, 3- (benzyloxycarbonyl group ethyl)-morpholine -2,5- diketone, (3S) -3- (benzyloxycarbonyl groups
Methyl) morpholine -2,5- diketone, (3S, 6RS) -3- (benzyloxycarbonyl-methyl) -6- Methyl-morpholine -2,5- diketone, (3s, 6RS) -3-
[4- (benzyloxycarbonyl amino) butyl] -6- Methyl-morpholine -2,5- diketone, (3S, 6RS) -3- to the thio methylol of methoxybenzyl -
6- Methyl-morpholine -2,5- diketone, 3-N- benzyloxycarbonyl groups lysyl--morpholine -2,5- diketone, 6- isopropyls-morpholine -2,5- bis-
Ketone, 6- isopropyl -3- Methyl-morpholine -2,5- diketone, maleic anhydride, succinic anhydride, dimethyl succinic acid acid anhydride, 2- methylene-fourth two
Anhydride, tetrafluoro succinic anhydride, glutaric anhydride, 3,3- tetramethyleneglutaric acid acid anhydrides, 3,3- dimethylated pentanedioic acid acid anhydrides, 2,2- dimethyl
Glutaric anhydride, 3- ethyl -3- methylglutaric acid acid anhydrides, hexafluoroglutaric anhydride, adipic anhydride, sebacic anhydride, N- carboxyls the third ammonia of-L-
Acid-ring inner-acid anhydride, 2- methoxyl group -2- oxygen -1,3,2- dioxaphospholane, 2- ethyoxyl -2- oxygen -1,3,2- dioxy phosphorus heterocycles
Pentane, 2- chloroethoxy -2- oxygen -1,3,2- dioxaphospholane, the chloro- 2- oxygen -1,3,2- dioxaphospholane of 2-, 2- alkynes
Propoxyl group -2- oxygen -1,3,2- dioxaphospholane, 5,5- dimethyl -2- oxygen -1,3,2- dioxaphospholane, 5,5- bis-
The chloro- 1,3,2- dioxaphosphorinanes -2- ketone of methyl -2-, ethylidene ethyl phosphonic acid ester EEP, ethylidene isobutyl group phosphate ester
Homopolymer or the copolymerization of EIBP, ethylidene 1-isobutyl-3,5-dimethylhexylphosphoric acid ELP, ethylidene octadecyl phosphate ester ESP and its derivant
Thing one or more, coating layer thickness be below 2mm;Or, Biodegradable slowly released and controlled-drug delivery system is loaded on into capsule
It is interior.
8. according to the preparation method of the Biodegradable slowly released and controlled-drug delivery system described in claim 6, it is characterised in that step
(1) in, drug solution concentration is controllable, and drug level is preferably 1~10mg/ml.
9. according to the preparation method of the Biodegradable slowly released and controlled-drug delivery system described in claim 6, it is characterised in that medicine is carried
The shape and size of body is arbitrarily adjusted, and drug loading is controllable therewith.
10. the application of the Biodegradable slowly released and controlled-drug delivery system described in a kind of claim 1, it is characterised in that the system is used
In operation suture thread, Antiadhesive film, tissue engineering bracket, subcutaneous implant, contraception implants, transdermal or inhalation.
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CN113117130A (en) * | 2021-01-13 | 2021-07-16 | 海南建科药业有限公司 | Surface treatment method for medical operation line |
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