CN106822066B - Minocycline sustained release preparation - Google Patents
Minocycline sustained release preparation Download PDFInfo
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- CN106822066B CN106822066B CN201710207548.7A CN201710207548A CN106822066B CN 106822066 B CN106822066 B CN 106822066B CN 201710207548 A CN201710207548 A CN 201710207548A CN 106822066 B CN106822066 B CN 106822066B
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- minocycline
- sustained release
- release preparation
- copolymer
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- 229960004023 minocycline Drugs 0.000 title claims abstract description 40
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 35
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 title claims abstract 19
- 239000000178 monomer Substances 0.000 claims abstract description 18
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 15
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003999 initiator Substances 0.000 claims abstract description 12
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- 229920005604 random copolymer Polymers 0.000 claims abstract description 10
- 239000010695 polyglycol Substances 0.000 claims abstract description 9
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical group O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims abstract description 9
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 8
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- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical group Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 claims description 29
- 229960002421 minocycline hydrochloride Drugs 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
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- 150000003839 salts Chemical class 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- 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
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of minocycline sustained release preparation, it is characterized in that, it is formed by degradable biological film with minocycline, the degradable biological film be using poly glycol monomethyl ether as initiator, using levorotatory lactide and 6-caprolactone as polyethylene glycol-polylactide obtained by monomer ring-opening polymerisation-polycaprolactone random copolymer, the number-average molecular weight of the random copolymer is 8.0 × 104~9.0 × 104In the range of, there is structural formula shown in following (1):Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
Description
Technical field
The present invention relates to a kind of minocycline sustained release preparations.
Background technique
Periodontitis is department of stomatology common disease, is the main reason for mankind lose tooth.It is mainly that machinery is controlled for slight periodontitis
It treats.With the progress of the state of an illness, periodontal tissue destruction is got worse, and oral pocket deepens, and simple mechanical treatment is extremely difficult to be satisfied with effect
Fruit is present in the pathogenic bacteria in gingiva tissue or in tissue of tooth and is difficult to remove completely.In recent years, antibiotic is applied to periodontal
More and more attention has been paid to the treatment of local sustained release drug becomes a kind of novel treatment method for scorching treatment.
Minocycline hydrochloride is clinically common periodontitis local sustained release drug, is efficient, quick-acting, long-acting semi-synthetic
Tetracycline novel formulation, drug-fast bacteria is few, has a broad antifungal spectrum, antibacterial activity are strong, easily permeates, has unique drug release profile, be four
Antibacterial activity is most strong in ring element family antibiotic and blood medicine effective time longest one kind.To the pathogenic bacteria height of all kinds of periodontitis
Sensitivity, and Collage Activitv can be inhibited, promote organization healing, with wide application and development space.Wang Yinfu[1]Pass through research
It confirms, Minocycline ointment meets after water is hardened and forms the envelope for having mesh sample, is conducive to delay preferably in oral pocket
On The Drug Release, and high local concentrations stabilization can be kept up to 7 days, while also the breakdown speed of alveolar bone can be made substantially to slow down, to reach
Long-acting treatment purpose.
Polycaprolactone (PCL), polylactide (PLLA) are common biodegradable polyesters, have good mechanicalness
It can, can blended, biocompatibility and degradability.Poly glycol monomethyl ether (mPEG) is used as good hydrophilic polymer,
Good biocompatibility, nontoxic, immunogenicity is low, can be excreted by kidney.
Xu Liangliang etc.[2]It is total that amphipathic caprolactone-ethylene glycol-lactide (PCELA) three block has been synthesized using the precipitation method
Polymers, but in the document, what is be prepared is the nano-micelle of copolymer, rather than biofilm, and without reference to will be total to
Polymers is used for sustained release preparation, the more research without reference to release in vitro, film forming etc..
Chen Hongli[3]Polycaprolactone/polyoxyethylene/polylactide terpolymer has been synthesized Deng using PEG 6000, has been copolymerized
The ratio of the different monomers of object is 14/14/72,25/25/50, and the document is also used for sustained release preparation without reference to by copolymer, and
And the document only has studied the biological degradability of copolymer, without reference to release property in the film forming of copolymer, oral cavity etc.
Research.
Zheng Zhang[4](gather in oneself etc. triblock copolymer (polycaprolactone-lactide)-polyethylene glycol-has been synthesized
Ester-lactide), i.e. PCLA-PEG-PCLA, the document has studied bio-safety performance, degradation property and the prevention of the polymer
The barrier action of post-operation adhesion, without reference to the film forming of copolymer, load pharmacological property and slow release.
Existing technical literature
[1] Comparative Analysis of Wang Yinfu Minocycline ointment and Tinidazole topical therapy periodontitis
[J] chinese medicine science, 2011,1 (24): 87-88.
[2] Xu Liangliang, Chen Qiang, Li Li wait the amphipathic copolymer nano micella of polycaprolactone/polyethyleneglycol/polylactide
Preparation and representation [J] material Leader, 2006,20 (11): 131-133.
[3] Chen Hongli, Bei Jianzhong, Wang Shenguo Biodegradable high molecular-polycaprolactone/polyoxyethylene/polylactide ternary
Research [J] macromolecule journal of copolymer conduct hydrolysis, 2000, (5): 626-631.
[4]Zheng Zhang,Jian Ni,Liang Chen,et al.Biodegradable and
thermoreversible PCLA-PEG-PCLA hydrogel as a barrier for prevention of post-
operative adhesion.
Biomaterials,2011,32(21):4725-4736.
Summary of the invention
Technical problems to be solved by the inivention
The present invention is directed to develop a kind of minocycline sustained release preparation with good slow releasing function.
For solving the scheme of above-mentioned technical problem
Inventors have found that with poly glycol monomethyl ether (mPEG) for initiator, levorotatory lactide (L-LA) and caprolactone (ε-
It CL is) mPEG-P (LLA-co-CL) (poly glycol monomethyl ether-polylactide-polycaprolactone) nothing of monomer ring-opening polymerisation preparation
Copolymer is advised, when the number-average molecular weight of the polymer is controlled 8.0 × 104~9.0 × 104In the range of, the weight of L-LA and ε-CL
When the ratio of multiple unit is 3 to 1, it can obtain that there is certain hydrophily and good mechanical strength while have both good load medicine
The degradable biological film of performance and medicine-releasing performance can be made by the degradable biological film and be made with good sustained release
Minocycline sustained release preparation.
Specifically, the present invention includes the following contents.
1. a kind of minocycline sustained release preparation, which is characterized in that it is formed by degradable biological film with minocycline, it is described
Degradable biological film is using poly glycol monomethyl ether as initiator, using levorotatory lactide and 6-caprolactone as monomer ring-opening polymerisation
Obtained by polyethylene glycol-polylactide-polycaprolactone random copolymer, the number-average molecular weight of the random copolymer 8.0 ×
104~9.0 × 104In the range of, and there is structural formula shown in following (1):
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
2. the minocycline sustained release preparation as described in above-mentioned (1), the minocycline can pharmaceutically be connect with minocycline
The form for the salt received provides.
3. the minocycline sustained release preparation as described in above-mentioned (2), the shape of the pharmaceutically acceptable salt of the minocycline
Formula is minocycline hydrochloride.
4. the minocycline sustained release preparation as described in any one of above-mentioned (1)-(3), which is characterized in that the initiator is poly-
Glycol monoethyl ether is mPEG 4000.
5. the minocycline sustained release preparation as described in any one of above-mentioned (1)-(3), which is characterized in that the copolymer
Molecular weight distribution is 1.5.
6. the minocycline sustained release preparation as described in any one of above-mentioned (1)-(3), which is characterized in that the copolymer
Number-average molecular weight is 8.1 × 104。
7. the minocycline sustained release preparation as described in any one of above-mentioned (1)-(3), which is characterized in that drugloading rate is
5wt%-10wt%.
8. a kind of preparation method of minocycline sustained release preparation, which is characterized in that weigh degradable biological film and minot
The pharmaceutically acceptable salt of ring element, is dissolved in chloroform and methanol respectively, stands after mixing well, after bubble eliminates plastic film mulch in
On polyfluortetraethylene plate, drying at room temperature rear demoulding, the degradable biological film be using poly glycol monomethyl ether as initiator, with
Levorotatory lactide and 6-caprolactone are polyethylene glycol-polylactide-polycaprolactone random copolymer obtained by monomer ring-opening polymerisation,
The number-average molecular weight of the random copolymer is 8.0 × 104~9.0 × 104In the range of, and there is structure shown in following (1)
Formula:
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
9. the preparation method of the minocycline sustained release preparation as described in above-mentioned (8), which is characterized in that the minocycline
Pharmaceutically acceptable salt is minocycline hydrochloride.
10. the preparation method of the minocycline sustained release preparation as described in above-mentioned (8) or (9), which is characterized in that the copolymerization
The number-average molecular weight of object is 8.1 × 104。
Invention effect
By the invention it is possible to provide a kind of minocycline sustained release preparation with good slow release effect, the minot
Ring element sustained release preparation has a biodegradable film, this kind of film has certain hydrophily and good mechanical strength, simultaneously
Have both good drug carrying ability and medicine-releasing performance.
Detailed description of the invention
Fig. 1 is mPEG-P (LLA-co-CL)1H NMR spectra
Fig. 2 is the infrared spectrogram of minocycline hydrochloride, polymer and medicine carrying membrane
A indicates that minocycline hydrochloride, b indicate that polymer, c indicate medicine carrying membrane
Fig. 3 is scanning electron microscope (SEM) figure on medicine carrying membrane surface under different multiples
A:54 times, B:1000 times, C:2000 times, D:4000 times
Fig. 4 is scanning electron microscope (SEM) figure on the medicine carrying membrane surface after stretching under different multiples
A:54 times, B:1000 times, C:2000 times, D:4000 times
Fig. 5 is the Bactericidal test result of minocycline hydrochloride sustained-release preparation made from copolymer 1
A indicates the antibacterial ring size to cariogenic bacteria streptococcus mutans (S.m), and B indicates the antibacterial ring size to Fusobacterium nucleatum (F.n)
Fig. 6 is the laser co-focusing experimental result picture of medicine carrying membrane
A, B indicates medicine carrying membrane to the antibacterial action (A:0wt%, B:10wt%) of Fusobacterium nucleatum biomembrane, and C, D are indicated
For 0wt% medicine carrying membrane to the antibacterial action (C: flcating germ, D: biomembrane) of streptococcus mutans, E, F indicate 10wt% medicine carrying membrane to change
The streptococcic antibacterial action of shape (E: flcating germ, F: biomembrane).
Specific embodiment
Hereinafter, the specific embodiment that present invention will be described in detail with reference to the accompanying.In addition, embodiments of the present invention and unlimited
Due to following embodiments, those skilled in the art can carry out within the scope of the technical concept of the present invention various changes and replace
It changes.
Embodiment
One, the preparation of mPEG-P (LLA-co-CL) polymer
1 material and equipment
1.1 experimental material
1.2 capital equipment
| Instrument title | Model | Manufacturer |
| Vacuum oven | XMTD-8222 | Jing Hong Co., Ltd |
| Oil pump | ZXZ-4 type | Shanghai De Ying vacuum Lighting Co., Ltd |
| Nmr analysis instrument | Bruker | Switzerland Bruker |
| Gel permeation chromatograph | Waters1515 | U.S. Waters |
2 experimental methods
The pre-treatment of 2.1 experimental raws
(1) 6-caprolactone: 6-caprolactone is poured into round-bottomed flask, weighs fraction of calcium hydride (CaH2) pour into wherein,
It is stirred to react 72 hours, removes micro-moisture, vacuum distillation obtains dry 6-caprolactone, and hermetically drying saves.
(2) toluene: a certain amount of sodium silk is added in toluene to be dried, is flowed back at 250 DEG C 7-8 hour, distillation
Obtain dry toluene, kept dry.
(3) L- lactide: the levorotatory lactide that weighs with scale is placed in the reaction ball bottle of 250ml, pours into appropriate volume
Dry toluene stirs at 105-110 DEG C, lactide monomer dissolved in toluene completely after, rapid dumps in beaker,
It is sealed with preservative film, is placed in refrigerator and recrystallizes, be precipitated to crystal, filtered using vacuum pump completely.Such recrystallization repeats two
It is secondary.The L- lactide of processing twice is contained in round-bottomed flask, suitable dry toluene is added, is stirred at reflux at 130 DEG C, to
Toluene flows back two hours from oil water separator.Solution is poured into beaker, is sealed with preservative film, is placed in refrigerator and recrystallizes,
It has just been precipitated to crystal, has been filtered using vacuum pump.Such to be repeated twice, last time, which filters, to be completed to use anhydrous ether
Product is evacuated three hours by elution with water pump, and the D-lactic acid monomer purified is stored in dry container after being sealed against
It is interior to be used in case of subsequent polymerization experiment.
(4) 4000 mPEG: mPEG4000 is contained in round-bottomed flask, and suitable dry toluene is added, and is stirred at 130 DEG C
Reflux is mixed, vacuum distillation removes toluene after toluene is from two hours of flowing back in oil water separator, obtains dry mPEG
4000。
In the present invention, the molecular weight of mPEG is too greatly, big in polymer terminal group role, in vivo cannot be by generation
It thanks, and degradation speed can be slack-off, therefore it is preferable to use mPEG4000.
The preparation of 2.2mPEG-P (LLA-co-CL) copolymer
It, will be through two kinds of monomers of aforementioned pretreated 6-caprolactone and L- lactide and initiator under the protection of argon gas
MPEG is quickly adding into reaction eggplant-shape bottle roasted in advance, is placed in 45 DEG C or so of oil bath and is vacuumized.Under the protection of argon gas,
Catalyst stannous iso caprylate toluene solution is added dropwise into reaction system, ventilation.It is 120~150 DEG C that polymerization bottle, which is placed on temperature,
It is polymerize in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, it is molten that suitable methylene chloride is added
Solution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is put at normal temperature
Vacuum oven in constant weight.
In the present invention, reaction temperature is preferably controlled in 120~150 DEG C, if be lower than 120 DEG C, 6-caprolactone monomer it is anti-
Answer activity lower, the ratio of 6-caprolactone is often below design proportion in the copolymer of preparation, and polymer also tends to assume that block
Characteristic.Temperature is more than 150 DEG C, i.e., under higher reaction temperature, the catalytic activity of stannous iso caprylate is substantially reduced, and is unfavorable for anti-
The progress answered.It is ideal reaction temperature at 140 DEG C.
Preparation example 1
It, will be through aforementioned pretreated 2.2278g 6-caprolactone and 4.2222g L- lactide two under the protection of argon gas
Kind monomer and initiator 0.3g mPEG 4000 are quickly adding into together in preparatory roasted reaction eggplant-shape bottle three times, are placed in 45
DEG C oil bath vacuumize 4h.Under the protection of argon gas, the stannous iso caprylate toluene solution of 1g/mol is added dropwise by micro syringe
32.25 μ l (0.5/1000th of monomer gross mass) are into reaction system, and ventilation is three times.It is 140 DEG C that polymerization bottle, which is placed on temperature,
It is polymerize for 24 hours in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, suitable dichloromethane is added
Alkane dissolution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is placed on often
To constant weight in vacuum oven under temperature, mPEG-P (LLA-co-CL) copolymer 1 is obtained.
Preparation example 2
It, will be through aforementioned pretreated 2.2304g 6-caprolactone and 4.2298g L- lactide two under the protection of argon gas
Kind monomer and initiator 0.3g mPEG 4000 are quickly adding into together in preparatory roasted reaction eggplant-shape bottle three times, are placed in 45
DEG C oil bath vacuumize 4h.Under the protection of argon gas, the stannous iso caprylate toluene solution of 1g/mol is added dropwise by micro syringe
32.22 μ l (0.5/1000th of monomer gross mass) are into reaction system, and ventilation is three times.It is 120 DEG C that polymerization bottle, which is placed on temperature,
One day night of polymerization is carried out in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, is added suitable two
Chloromethanes dissolution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is put
To constant weight in vacuum oven at normal temperature, mPEG-P (LLA-co-CL) copolymer 2 is obtained.
Preparation example 3
It, will be through aforementioned pretreated 2.2232g 6-caprolactone and 4.2152g L- lactide two under the protection of argon gas
Kind monomer and initiator 0.3g mPEG 4000 are quickly adding into together in preparatory roasted reaction eggplant-shape bottle three times, are placed in 45
DEG C oil bath vacuumize 4h.Under the protection of argon gas, the stannous iso caprylate toluene solution of 1g/mol is added dropwise by micro syringe
32.28 μ l (0.5/1000th of monomer gross mass) are into reaction system, and ventilation is three times.It is 150 DEG C that polymerization bottle, which is placed on temperature,
One day night of polymerization is carried out in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, is added suitable two
Chloromethanes dissolution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is put
To constant weight in vacuum oven at normal temperature, mPEG-P (LLA-co-CL) copolymer 3 is obtained.
The characterization of 2.3 polymer
2.3.1 spectral analysis of the nuclear magnetic resonance (NMR)
1H NMR is used to characterize the monomer ratio and sequential structure of mPEG-P (LLA-co-CL) copolymer of preparation
Distribution.Concrete operations are as follows: weighing mPEG-P (LLA-co-CL) copolymer of about 5mg, be dissolved in CDCl3In, using Germany
Bruker AV 400MHz spectral analysis of the nuclear magnetic resonance instrument tests mPEG-P (LLA-co-CL's)1H NMR.In nucleus magnetic hydrogen spectrum figure
In obtain in mPEG-P (LLA-co-CL) copolymer proton hydrogen on molecule go out peak position and relative integral peak area, so as to
To determine the structure of mPEG-P (LLA-co-CL) copolymer.
Hereinafter, the structure elucidation process of copolymer is described in detail by taking mPEG-P (LLA-co-CL) copolymer 1 as an example.Fig. 1 is
MPEG-P (LLA-co-CL) copolymer 11H NMR spectra, the chemistry of all protons go out peak position and are labeled in it one by one
In.From1H NMR spectra can be seen that in mPEG-P (LLA-co-CL) copolymer 1, the proton appearance in L-LA unit be g and
H, the appearance of each proton is labeled as b, c, d, e, f in 6-caprolactone structural unit, and the peak position that goes out of mPEG is a.
The appearance of two kinds of monomers is specific as follows: chemical shift appearance of all protons on nucleus magnetic hydrogen spectrum in caprolactone units
Position is respectively 1.35ppm, 1.65ppm, 2.31-2.39ppm and 4.06-4.14ppm, corresponds respectively to the matter on γ methylene
Proton (e and c), the proton (b) on α methylene and the proton (f) on ε methylene on sub (d), β and δ methylene.It is left-handed
Chemistry of all Hydrogen Protons on nuclear magnetic spectrogram goes out peak position respectively in 1.49-1.55ppm and 5.05- in lactide repeat unit
Between 5.18ppm, corresponding thereto be Hydrogen Proton (h) on methyl and the Hydrogen Proton (g) on methine.b,c,d,e,f,g,
H be CL and LA influence each other it is lower caused by all kinds of inclined peaks.
By above-mentioned spectral analysis of the nuclear magnetic resonance it is found that structure such as following formula (1) institute of mPEG-P (LLA-co-CL) copolymer 1
Show:
Wherein, the ratio of L-LA and ε-CL repetitive unit is 3:1.
With with above-mentioned 2.3.1 same method, to the copolymer 2 as made from preparation example 2 and as made from preparation example 3 altogether
Polymers 3 is characterized, as the result is shown: copolymer 2,3 also has structure shown in formula (1).
2.3.2 gel permeation chromatograph (GPC)
The number-average molecular weight (Mn) and its molecular weight distribution (PDI) of mPEG-P (LLA-co-CL) copolymer are using the U.S.
The gel chromatography analyzer of the model water1515 of Waters, using THF as eluting solvent, the flow velocity of 1mL/min into
Row measurement.
By measuring above, the number-average molecular weight and molecular weight distribution of mPEG-P (LLA-co-CL) copolymer such as 1 institute of table
Show.
Table 1:
| Copolymer 1 | Copolymer 2 | Copolymer 3 | |
| Number-average molecular weight (Mn) | 80678 | 81004 | 81596 |
| Molecular weight distribution (PDI) | 1.5 | 1.5 | 1.5 |
Here, the ratio of lactide and caprolactone repetitive unit is preferably 3:1 in mPEG-P (LLA-co-CL) copolymer,
And the number-average molecular weight of copolymer is preferably in the range of 80,000~90,000, inventor it was unexpectedly observed that when the conditions are satisfied,
The minocycline hydrochloride oral cavity sustained release preparation as made from the co-polymer membrane can be provided simultaneously with long-acting sustained release performance with it is good
Mechanical property (film forming), and both performances are particularly important for oral cavity sustained release preparation.
Two, the preparation of Dynacin
1 experimental section
1.1 materials and equipment
1.1.1 experimental material
Minocycline hydrochloride, yellow crystalline powder, odorless, bitter, purity 99% (Mayan reagent Co., Ltd)；
Methanol, colourless transparent liquid, the upper smooth Science and Technology Ltd. of Haitai；
Chloroform, colourless transparent liquid, Sinopharm Chemical Reagent Co., Ltd.；
Brain heart infusion (BHI), U.S. company BD；
Agar powder (lot number: 110914), Shanghai Bai Ao Biotechnology Co., Ltd；
Citric acid, Shantou City's brilliance laboratory；
Disodium hydrogen phosphate dodecahydrate, Sinopharm Chemical Reagent Co., Ltd.；
PH precision test paper (6.4~8.0), Sinopharm Chemical Reagent Co., Ltd.；
International standard bacterial strain streptococcus mutans (UA159), Fusobacterium nucleatum (AT25586), Shanghai City dentistry emphasis
Laboratory Microbiological Lab provides.
1.1.2 capital equipment
JA2003N electronic balance (Shanghai Precision Scientific Apparatus Co., Ltd)；
Magnetic stirring apparatus (B11-3, Shanghai Si Le Instrument Ltd.)；
PH tester (Shanghai Precision Scientific Apparatus Co., Ltd)；
Vernier caliper (precision 0.02mm, Shanghai Measuring and Cutting Tools Plant)；
Constant incubator (SANYO, SANYO GS mechanical & electrical corporation, Japan)；Anaerobic culture box (Whitley DG250, Don
Whitley scientific company, Britain)；
Spectrophotometer (UV-1601, Shimadzu company, Japan).
1.2 experimental method
1.2.1 the preparation of medicine carrying membrane
Precision weighs 1.5g mPEG-P (LLA-co-CL) and appropriate bulk pharmaceutical chemicals minocycline hydrochloride, is dissolved in 15mL chlorine respectively
In imitative and 1mL methanol, then minocycline hydrochloride solution is slowly added dropwise in polymer solution, is stood after mixing well, to
Bubble eliminates rear plastic film mulch on polyfluortetraethylene plate, 72 hours rear demouldings of drying at room temperature, obtained content of dispersion be respectively 5wt%,
Three kinds of medicine carrying membranes of 8wt% and 10wt% and the blank film of non-drug containing.Diaphragm is broken into the circle of 6mm diameter with punch
Diaphragm, ultraviolet light irradiation 30min sterilizing, is sealed in spare in clean brown bottle.Every 0.5~1.0mg of medicine film drug containing.
1.2.2SEM the surface topography of film is characterized
Every group of film randomly selects the small strip for being cut into 3mm × 10mm size, in scanning electron microscope after metal spraying processing
On the surface topography of every cluster film is analyzed.
1.2.3 the physicochemical property test of medicine carrying membrane
1.2.3.1 quality uniformity measures
A film in every group of film is randomly selected, different location cuts out the diaphragm of 1cm × 1cm at the 5 of film, uses respectively
Electronic balance weighing calculates average value.
1.2.3.2 the thickness uniformity measures
A film in every group of film is randomly selected, the thickness of 5 different locations of film is measured with micrometer caliper,
Calculate average value.
1.2.3.3 surface pH measures
Each group film is cut into the diaphragm of same size 1cm × 1cm, every group Duplicate Samples 5, is placed in the culture accordingly numbered
It in ware, injects McIlvaine buffer (pH 6.6), after impregnating 2 hours, is measured with PH test paper.
1.2.3.4 Measuring Mechanical Properties
According to GB/T 1040.3-2006 " the measurement third portion of plastic tensile performance: the experimental condition of film and thin slice ",
Film is cut by wide 4mm using standard module, the dumbbell shape sample of gauge length 25mm, every group Duplicate Samples 5.After sample is cut into,
Normal temperature and pressure is stored 12 hours, and stress caused by cutting process is discharged.Rate of extension 200mm/min, test temperature (25 ± 2)
DEG C, it is averaged.
1.2.4 the medicament slow release performance research of medicine carrying membrane
1.2.4.1McIlvaine the preparation of buffer
Precision weighs disodium hydrogen phosphate 35.814g, anhydrous citric acid 9.6065g, uses 500ml deionized water respectively
It is dissolved, matches to obtain 0.2mol/L Na2HPO4After 0.1mol/L citric acid solution, then 145.5ml 0.2mol/L is taken respectively
Na2HPO4The McIlvaine buffer solution that pH value is 6.6 is mixed to prepare with 54.5ml 0.1mol/L citric acid.
1.2.4.2 the determination of Detection wavelength
The minocycline hydrochloride solution for preparing 0.02mg/ml carries out UV absorption wave in 200~400nm wave-length coverage
Long scan, a length of 345nm of the maximum absorption wave of minocycline hydrochloride.
1.2.4.3 interference experiment
10mg/ml mPEG-P (LLA-co-CL) solution is prepared, UV absorption is carried out in 200~400nm wave-length coverage
Length scanning is found at 345nm wavelength without absorption, thus can exclude medicine film auxiliary material at the wavelength to minocycline hydrochloride medicine
The interference of analyte detection.
1.2.4.4 the foundation of standard curve
Precision weighs minocycline hydrochloride 10mg and is dissolved in 50ml measuring bottle, after constant volume, take respectively 100ul, 250ul,
375ul, 500ul, 750ul, 1000ul, 1250ul and 1500ul constant volume in 10ml measuring bottle, obtain concentration be respectively 2.0ug/ml,
The minocycline hydrochloride of 5.0ug/ml, 7.5ug/ml, 10.0ug/ml, 15ug/ml, 20ug/ml, 25ug/ml and 30ug/ml are dilute
Liquid is released, trap is surveyed at 345nm, is mapped with concentration C to trap A, and carry out linear regression.
1.2.4.5 medicament slow release is tested
Precision weighs medicine carrying membrane piece (medicine content is respectively 0.5mg, 0.8mg, 1.0mg) and is put into 200ml conical flask, is added
The Mcllvaine buffer of 50ml is placed in 37 DEG C of full incubators and stands.In particular point in time 0.5h, 1h, 2h, 4h, 8h, 12h,
For 24 hours, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h and 336h liquid-transfering gun from
5ml McIlvaine buffer is accurately measured in conical flask, while the fresh McIlvaine that 5ml temperature is 37 DEG C is added and buffers
Liquid keeps total volume constant, with the absorbance of ultraviolet specrophotometer measurement drug, calculates cumulative release amount percentage.Every group
3 parallel laboratory tests are carried out, experimental result is averaged.
1.2.5 the in-vitro antibacterial performance study of medicine carrying membrane
1.2.5.1 the preparation of bacterium solution
Periodontal Pathogens Fusobacterium nucleatum (F.nucleatum) is selected in experiment, cariogenic bacteria streptococcus mutans (S.mutans),
With aseptic inoculation ring picking BHI agar plate surface monoclonal bacterium colony in 3ml BHI fluid nutrient medium, S.mutans is in general
Logical incubator, F.nucleatum are cultivated for 24 hours in 37 DEG C of anaerobic culture box.Dyeing microscopic examination is pure culture, and spectrophotometer is by bacterium
Liquid concentration is adjusted to 1 × 106CFU/ml is spare.
1.2.5.2 Bactericidal test
In superclean bench, the BHI Solid agar culture disinfected is poured into sterile petri dish, cooling obtains
After culture medium flat plate, with liquid-transfering gun draw 50ul bacterium solution be added dropwise on culture medium flat plate, sterile L stick push away it is even, be made containing bacterium cultivate
Base plate.It is put into the circular film disinfected is equidistant in plate containing bacterium culture medium, after being placed with, with the light press mold of aseptic nipper
Piece contacts it suitably with agar surface.It is control with mPEG-P (LLA-co-CL) blank film, makees 3 culture dishes in parallel.Respectively
It is inverted in 37 DEG C of anaerobic culture boxes, observes result afterwards for 24 hours.With vernier caliper measurement antibacterial circle diameter.Experiment 3 times is repeated, is taken
Average value.
1.2.6 the vitro cytotoxicity research of medicine carrying membrane
1.2.6.1 leaching liquor preparation and grouping
Will 0wt%~10wt%MH/mPEG-P (LLA-co-CL) medicine film ultraviolet lighting 2h disinfection after by surface of test piece product and
The ratio between culture solution is 6cm2Medicine film, is put into the sterile centrifugation tube of the cell culture fluid of DMEM containing 10ml by/ml (ISO10993-12)
In, it is placed in 37 DEG C of constant-temperature tables and places 24 ± 2h.Cell leaching liquor is filtered with the filter that diameter is 0.22um after culture, then dilute
Release be made into respectively 50%, 100% material leaching liquor.Experimental setup positive control and negative control, addition dimethyl sulfoxide group are
Positive controls, addition cell culture fluid group are negative control group.
1.2.6.2 cytotoxicity test (MTT)
Using the method for Cell culture invitro, according to ISO10993-5, experiment uses the MTT method of high sensitivity
(mtt assay) carries out vitro cytotoxicity detection.Periodontal ligament fibroblasts in vitro is selected in experiment, and cell is derived from three volunteers, age
Between 20-25 years old, the periodontium of the third molar of extraction, subculture is to third in DMEM cell culture fluid
In generation, being configured to concentration is 4 × 103/ ml cell suspension, is then inoculated in 96 orifice plates, every hole 200ul, every group of 6 holes.37 DEG C of perseverances
After temperature culture for 24 hours, inhales and abandon culture solution, 50%, 100% two kind of concentration material leaching liquor is separately added into 96 orifice plates, every hole
200ul.It is cultivated for 24 hours in 37 DEG C of cell constant temperature casees, every hole is added 20ul (5mg/mL) MTT solution and is protected from light culture 4h.It inhales and abandons respectively
Boreliquid, every hole are added 200ul dimethyl sulfoxide, shake 10min at room temperature, in measuring each hole on enzyme linked immunological instrument in 490nm
The absorbance value (OD) at place, experiment is in triplicate.Calculate the relative activity (RGR) of cell in each group.
1.2.7 the laser co-focusing experiment of medicine carrying membrane
By 2.4 × 2.4cm2Coverslip is placed in 6 orifice plates, and every hole is separately added into about 2ml 105The streptococcus mutans of CFU/ml
With Fusobacterium nucleatum bacterium solution, Anaerobic culturel forms biomembrane afterwards for 24 hours, after normal saline flushing 2 times, is contained respectively with different pharmaceutical
The medicine carrying membrane leaching liquor of amount carries out processing 30min, and blank film leaching liquor processing group is as a control group.Meanwhile it is floating in former 6 orifice plates
The medicine film leaching liquor of trip bacterium equivalent volumes is handled.After 30min, biological membrane sample gently rinses 5 times with physiological saline, together
When flcating germ collect mix, be protected from light, be separately added into LIVE/ BacLightTMBacterial Viability Kit is thin
Bacterium survives kit fluorescence dye liquor, coverslip is placed under laser confocal microscope after 15min and is observed.488nm/561nm light
After source excitation, viable bacteria issues green fluorescence in conjunction with SYTO9, and dead bacterium nucleus DNA issues red fluorescence in conjunction with PI.Experimental group
Respectively contain three samples.
2 results
2.1 appearance
Co-polymer membrane obtained by preparation example 1~3 is yellow sheet type film, bright and clean complete, consistency of thickness, and color is equal
It is even, without obvious bubble.
2.2 film surface micro-analysis
Fig. 2 is the infrared spectrogram of minocycline hydrochloride, polymer and medicine carrying membrane, and wherein curve a is minocycline hydrochloride,
Curve b is mPEG-P (LLA-co-CL) polymer, and curve c is medicine carrying membrane, and infrared spectrogram is shown, nothing between main ingredient and polymer
Interaction, therefore it may be speculated that drug and polymer be it is compatible, film forming can be prepared.
Fig. 3 be different multiples under 10wt% carry medicine co-polymer membrane surface scanning electron microscope (SEM) figure, wherein A, B,
C, D be respectively 54 times, 1000 times, 2000 times, the medicine carrying membrane surface microscopic figure under 4000 times of mirrors, it is seen then that drug crystallization particle from
Assembling is orderly embedded in thin polymer film in disc-shaped.
Quality, thickness and the surface p H analysis of 2.3 films
The quality and the thickness uniformity of medicine film are the direct factors for influencing film drug dose.The results show that of the invention is total to
The quality and thickness of polymers medicine film are all more uniform, and can be obtained according to specific needs by solution film casting method.Medicine carrying membrane table
Face pH value range is between 6.7~7, and close with the pH value 6.6 of level in gingival sulcus fluid, partial neutral, the results are shown in Table 2.
Table 2: the physical and chemical performance of different films
The Evaluating Mechanical Properties of 2.4 medicine carrying membranes
The mechanical property of medicine carrying membrane has been done and has tested (table 3), wherein the elongation at break of medicine carrying membrane is very high, peak load
It is smaller, tensile strength is smaller, i.e. the toughness of material is fine, more soft, as the load medicine film in oral pocket, can be very good
It is bonded affected part.Meanwhile to medicine carrying membrane shooting Electronic Speculum (Fig. 4) after stretching as can be seen that white particle part is hydrochloric acid rice really
Promise ring crude granule, black portions are in extension test, and the hole that particle leaves on polymer after coming out, wherein A, B, C, D divide
Not Wei 54 times, 1000 times, 2000 times, stretch under 4000 times of mirrors after medicine carrying membrane surface microscopic figure.
The mechanical property of 3. minocycline hydrochloride pharmaceutical film of table
| Medicament contg | Peak load (N) | Tensile strength (MPa) | Elongation at break (%) | Elasticity modulus (N/mm) |
| 5wt% | 4.98 | 7.00 | 906.33 | 1.10 |
| 8wt% | 4.22 | 7.27 | 972.93 | 1.01 |
| 10wt% | 4.10 | 7.12 | 977.66 | 1.05 |
The sustained release performance of 2.5 medicine carrying membranes is evaluated
2.5.1 minocycline hydrochloride standard curve
Using minocycline hydrochloride concentration C as abscissa, the absorbance A at 345nm is that ordinate obtains regression equation: A=
0.0274C+0.0014(r2=0.9999), at 345nm, the concentration C of minocycline hydrochloride is in 2.0~24.0ug/ml range
It is interior to have good linear relationship with absorbance A.
2.5.2 external sustained release experiment
The absorbance that each time point measures measures drug release amount by regression equation, calculates cumulative release amount percentage, with accumulation
Drug release amount percentage maps to the time.Table 4 is that the different proportion minocycline hydrochloride pharmaceutical film as made from copolymer 1 is external
It is sustained result.Table 4 shows that pharmaceutical release time shortens, 10wt% hydrochloric acid minot with the increase of minocycline hydrochloride content
Ring element medicine film slow-release time is two weeks, and with the increase of medicament contg, drug accumulation release rate is also obviously increased.
4. minocycline hydrochloride pharmaceutical film release in vitro result (n=3, pH 6.6) of table
The anti-microbial property of 2.6 medicine carrying membranes is evaluated
2.6.1 antibacterial ring size is tested
The anti-microbial property of the minocycline hydrochloride sustained-release preparation as made from copolymer 1 is evaluated.
The antibacterial tests of minocycline hydrochloride sustained-release preparation show that each culture medium flat plate bacterial growth is good, medicine carrying membrane pair
S.m and F.n has antibacterial ring size generation.Antibacterial effect is gradually increased with the increase of medicament contg, and inhibition of the medicine film to F.n
Effect is better than the inhibiting effect to S.m.As a result see Fig. 5, wherein A is the antibacterial ring size to cariogenic bacteria streptococcus mutans (S.m), and B is
To the antibacterial ring size of Fusobacterium nucleatum (F.n).
2.6.2 laser co-focusing is tested
At blank film leaching liquor group (Fig. 6 A, C, D), streptococcus mutans, the flcating germ of Fusobacterium nucleatum and biomembrane swash
Light is copolymerized in burnt picture, and green fluorescence has been almost full with whole visual field, and in the processing of the medicine carrying membrane leaching liquor of different pharmaceutical content
In group (Fig. 6 B, E, F), green and red fluorescence respectively account for certain proportion and have part to overlap into crocus, that is, the overlapping for the dead bacterium that lives,
With the increase of medicament contg, biomembrane and flcating germ compare control group, and dead bacterium is in the majority, illustrates minocycline hydrochloride medicine film pair
The biomembrane and flcating germ of streptococcus mutans and Fusobacterium nucleatum have very strong inhibiting effect.
The vitro Cytotoxicity Evaluation of 2.7 medicine carrying membranes
Grade assessment (Pyatyi) is carried out to the cytotoxicity of material.0 grade of cytotoxicity: RGR >=100%, cytotoxicity 1
Grade: 75%≤RGR≤99%, 2 grades of cytotoxicity: 50%≤RGR≤74%, 3 grades of cytotoxicity: 5%≤RGR≤49%, carefully
4 grades of cellular toxicity: 1%≤RGR≤24%, cytotoxicity 5 grades: RGR=0.Evaluation of result: it if experimental result is 0 or 1 grade, indicates
Belong to passing material；Experimental result is 2 grades, and combination cell specific form to carry out overall merit；Experimental result is 3-5 grades, then
Material is unqualified.It the results are shown in Table 5,6.
The OD value of MH/mPEG-P (LLA-co-CL) each group medicine film leaching liquor when table 5.100% and 50% concentration
Table 6.MH/mPEG-P (LLA-co-CL) group of cells is with respect to appreciation rate and toxicity level
By table 5,6 as it can be seen that in addition to 100% concentration 10wt%MH/mPEG-P (LLA-co-CL) cell leaching liquor cell phase
To appreciation rate 87.45%, cytotoxicity grade is 1 grade, other 50% and 100% cell leaching liquor cells are equal with respect to appreciation rate
Greater than 100%, cytotoxicity grade is 0 grade.
Claims (10)
1. a kind of minocycline sustained release preparation, which is characterized in that it is formed by degradable biological film with minocycline, it is described to drop
Solving biofilm is to be obtained using poly glycol monomethyl ether as initiator, using levorotatory lactide and 6-caprolactone as monomer ring-opening polymerisation
Polyethylene glycol-polylactide-polycaprolactone random copolymer, the number-average molecular weight of the random copolymer is 8.0 × 104~
9.0×104In the range of, and there is structural formula shown in following (1):
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
2. minocycline sustained release preparation as described in claim 1, the minocycline is with the pharmaceutically acceptable of minocycline
Salt form provide.
3. minocycline sustained release preparation as claimed in claim 2, the form of the pharmaceutically acceptable salt of the minocycline
It is minocycline hydrochloride.
4. minocycline sustained release preparation as claimed in any one of claims 1-3, which is characterized in that the poly- second two of initiator
Alcohol monomethyl ether is mPEG 4000.
5. minocycline sustained release preparation as claimed in any one of claims 1-3, which is characterized in that the molecule of the copolymer
Amount is distributed as 1.5.
6. minocycline sustained release preparation as claimed in any one of claims 1-3, which is characterized in that the number of the copolymer is equal
Molecular weight is 8.1 × 104。
7. minocycline sustained release preparation as claimed in any one of claims 1-3, which is characterized in that drugloading rate 5wt%-
10wt%.
8. a kind of preparation method of minocycline sustained release preparation, which is characterized in that weigh degradable biological film and minocycline
Pharmaceutically acceptable salt, be dissolved in chloroform and methanol, stood after mixing well respectively, the plastic film mulch Yu Jusi after bubble eliminates
On vinyl fluoride plate, drying at room temperature rear demoulding, the degradable biological film is using poly glycol monomethyl ether as initiator, with left-handed
Lactide and 6-caprolactone are polyethylene glycol-polylactide-polycaprolactone random copolymer obtained by monomer ring-opening polymerisation, described
The number-average molecular weight of random copolymer is 8.0 × 104~9.0 × 104In the range of, and there is structural formula shown in following (1):
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
9. the preparation method of minocycline sustained release preparation as claimed in claim 8, which is characterized in that the medicine of the minocycline
Acceptable salt is minocycline hydrochloride on.
10. the preparation method of minocycline sustained release preparation as claimed in claim 8 or 9, which is characterized in that the copolymer
Number-average molecular weight is 8.1 × 104。
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| CN101756908A (en) * | 2010-01-25 | 2010-06-30 | 沈阳药科大学 | Hydroxyapatite micro-sphere with polyester coating and preparation method thereof |
| CN103254442A (en) * | 2013-04-28 | 2013-08-21 | 天津大学 | Disulfide bond linked polyester comb-type graft copolymer as well as preparation method and application thereof |
| CN104415029A (en) * | 2013-08-20 | 2015-03-18 | 苏州雷纳药物研发有限公司 | Andrographolide polymer micelle, preparation method and medicinal application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756908A (en) * | 2010-01-25 | 2010-06-30 | 沈阳药科大学 | Hydroxyapatite micro-sphere with polyester coating and preparation method thereof |
| CN103254442A (en) * | 2013-04-28 | 2013-08-21 | 天津大学 | Disulfide bond linked polyester comb-type graft copolymer as well as preparation method and application thereof |
| CN104415029A (en) * | 2013-08-20 | 2015-03-18 | 苏州雷纳药物研发有限公司 | Andrographolide polymer micelle, preparation method and medicinal application thereof |
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