CN105496943B - Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place and preparation method thereof - Google Patents

Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place and preparation method thereof Download PDF

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CN105496943B
CN105496943B CN201510940200.XA CN201510940200A CN105496943B CN 105496943 B CN105496943 B CN 105496943B CN 201510940200 A CN201510940200 A CN 201510940200A CN 105496943 B CN105496943 B CN 105496943B
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gel
pge2
plga
mss
place
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CN105496943A (en
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白艳洁
徐晖
白雪涛
梁再赋
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    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0063—Periodont

Abstract

The present invention relates to responsive to temperature type field of gel in place, specially a kind of nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place and preparation method thereof.According to parts by weight, nanometer hydroxyapatite：0.3~1 part, PGE2-PLGA-MSs：0.005~0.02 part, Lutrol F127：0.5~5 part, water：5~15 parts.Take the Lutrol F127 of formula ratio, it spreads by several times in water, stirs to being uniformly dispersed, be placed in refrigerator and refrigerate 12~24 hours, nanometer hydroxyapatite is added, ice bath, it is uniform using ultrasonic probe progress ultrasonic disperse, PGE2-PLGA-MSs is added, it stirs evenly, it stands, forms nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place, room temperature preservation.Low-viscosity drug administration by injection at room temperature is locally changed into gel in injection site, extends active constituent in the effect of periodontal local retention time to realize.

Description

Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place and preparation method thereof
Technical field
The present invention relates to responsive to temperature type field of gel in place, specially a kind of nanometer hydroxyapatite-PGE2-PLGA- MSs hydridization gel in place and preparation method thereof.
Background technique
Lidocaine, poly lactic coglycolic acid (PLGA) microballoon are adulterated Lip river sand on the berth by Pen-Chung Chen etc. 407 (English name of nurse：Poloxamer, trade name：Pluronic Pluronic F127 or Lutrol F127) responsive to temperature type exists In the gel of position, abbreviation Lutrol F127 gel in place.After the drug administration by injection of sciatic nerve position, to Sensory and motor block Duration is obviously longer than simple lidocaine microsphere, this result be attributable to gel high viscosity bring sustained release and it is stagnant Stay effect.For periodontal drug administration by injection, extend the local retention time of preparation, so that it is severeer for playing more preferably therapeutic effect Challenge.
Currently, even being had not been reported about hydroxyapatite (HAP) with PGE2-PLGA-MSs hybrid system.
Summary of the invention
The purpose of the present invention is to provide a kind of nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place and its Preparation method reaches the local retention time for extending preparation, to play more preferably therapeutic effect.
The technical scheme is that：
A kind of nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place, according to parts by weight, nano hydroxyapatite Lime stone：0.3~1 part, PGE2-PLGA-MSs：0.005~0.02 part, Lutrol F127：0.5~5 part, water：5~15 parts.
Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization the gel in place, according to parts by weight, nano-hydroxy Apatite：0.5 part, PGE2-PLGA-MSs：0.01 part, Lutrol F127：2 parts, water：8 parts.
The preparation method of the nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place, takes formula ratio Lutrol F127 spreads in water by several times, stirs to being uniformly dispersed, be placed in refrigerator and refrigerate 12~24 hours, nano-hydroxy is added Apatite, ice bath is uniform using ultrasonic probe progress ultrasonic disperse, and PGE2-PLGA-MSs is added, stirs evenly, stands, is formed Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place, room temperature preservation.
The preparation method of the nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place, by nano hydroxyapatite Lime stone and PGE2-PLGA-MSs are entrained in the concentrated solution of Lutrol F127, the feature being gelled using its reverse temperature sensitivity： It is mobility liquid under low temperature, increases the temperature to 25 DEG C the above are gel, at room temperature low-viscosity drug administration by injection, in injection site Part is changed into gel, extends active constituent in the effect of periodontal local retention time to realize.
The invention has the advantages and beneficial effects that：
1, using HAP (hydroxyapatite) and PGE2-PLGA-MSs, (PGE2-PLGA-MSs is load prostate to the present invention The poly lactic coglycolic acid microballoon of plain E2) hydridization, the slowly releasing effect and hydroxyapatite nano of PLGA microballoon is utilized The osteoinductive and the two acid-base neutralization effect of particle, while microballoon preparation procedure is simplified, more conducively control influences real The unfavorable factor tested.In addition, poloxamer188 increases medicine as drug media, because of its unique temperature back reaction feature Object preferably plays the permanent mechanism of drug in the locally viscous time, therefore will have good development prospect.
2, the PGE2 of low concentration can increase self-bone grafting ability, and the PGE2 of high concentration can accelerate local bone resorption to improve Orthodontic Tooth Movement speed, therefore make full use of the dual-sustained-release mechanism and hydroxyapatite nano of PLGA and poloxamer188 The dual self-bone grafting mechanism of particle and appropriate PGE2 will provide the treatment of the department of stomatology and some bone related diseases of orthopaedics new Direction improves therapeutic effect and shortens treatment time, therefore will be with far-reaching clinical meaning.
Detailed description of the invention
Figure 1A-Fig. 1 D, Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization are coagulated in place The rheological curve of glue.Elastic modulus G ' (■), loss moduli G " (■) and angular frequency ang.frequency (rad ﹒ s-1) between Functional relation.Wherein, Figure 1A is Lutrol F127 gel in place (15 DEG C)；Figure 1B is Lutrol F127 gel (34 in place ℃)；Fig. 1 C is nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place (15 DEG C)；Fig. 1 D is nano-hydroxy-apatite Stone-PGE2-PLGA-MSs hydridization gel in place (34 DEG C).
Fig. 2A-Fig. 2 B, Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization are coagulated in place Phase angle delta (degrees) and angular frequency ang.frequency (the rad ﹒ s of glue-1) between functional relation (15 DEG C of ■, ● 34 ℃).Wherein, Fig. 2A is Lutrol F127 gel in place；Fig. 2 B is that nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization is in place Gel.
Fig. 3, Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place are answered Number viscosity [η *] (pa.s) and angular frequency ang.frequency (rad ﹒ s-1) between functional relation.Wherein, () Lutrol F127 gel in place (15 DEG C), (Δ) Lutrol F127 gel in place (34 DEG C), (■) nanometer hydroxyapatite-PGE2- PLGA-MSs hydridization gel in place (15 DEG C), (▲) nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel (34 in place ℃)。
Fig. 4 A- Fig. 4 D, Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hybrid gel Temperature-responsive gelling phenomenon in place；Wherein, Fig. 4 A is Lutrol F127 gel in place (15 DEG C)；Fig. 4 B is that Lutrol F127 exists Position gel (34 DEG C)；Fig. 4 C is nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place (15 DEG C)；Fig. 4 D is nanometer Hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place (34 DEG C).
Specific embodiment
In a specific embodiment, nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization of the present invention gel (in place Situ gel) preparation and characterization process it is as follows：
One, the preparation of nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place (in situ gel)
Nanometer hydroxyapatite and PGE2-PLGA-MSs are entrained in the concentrated solution of poloxamer188 by experiment, utilize it The feature (being mobility liquid under low temperature, increasing the temperature to 25 DEG C, the above are gels) of reverse temperature sensitivity gelling, can be in room temperature Lower low-viscosity drug administration by injection is locally changed into gel in injection site, extends active constituent in periodontal local retention to realize The effect of time.
The Lutrol F127 for taking formula ratio, spreads in water by several times, is slowly stirred to being uniformly dispersed, is placed in refrigerator and refrigerates Overnight, nanometer hydroxyapatite is added, ice bath, carrying out ultrasonic disperse 4min using ultrasonic probe, (5s-5s is meant that：Ultrasound 5 Second, stop 5 seconds, add up to 4 minutes), PGE2-PLGA-MSs is added, stirs evenly, stands, forms nanometer hydroxyapatite-PGE2- PLGA-MSs hydridization gel in place, room temperature preservation.
The formula composition of 1 nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place of table
Formula Nanometer hydroxyapatite, g PGE2-PLGA-Mss, g Lutrol F127, g Water, ml
1 0.01 2 8
2 0.5 0.01 2 8
Wherein, formula 1 is Lutrol F127 gel in place, and formula 2 is miscellaneous for nanometer hydroxyapatite-PGE2-PLGA-MSs Change gel in place.
Two, the characterization of nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place
It takes gel sample in place to be placed on the sample stage of rheometer, using plate (diameter 40mm) model, answers angular frequency 0.1~100rads of range-1, when measuring 15 DEG C and 34 DEG C respectively, record shearing stress calculates different with the variation of shear rate Viscosity when shear rate.
1, the rheology of Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place Curve
At 15 DEG C, Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place Loss moduli and elasticity modulus under different angular frequencies is all smaller, and loss moduli increases with angular frequency and increases (see Figure 1A, figure 1C), the feature of viscous liquid is shown.At 34 DEG C, Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2- PLGA-MSs hydridization gel elastomer modulus in place and loss moduli are all larger (see Figure 1B, Fig. 1 D), show typical gel Rheological properties.
2, the phase angle of Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place With angular frequency (rad ﹒ s-1) between functional relation
At 15 DEG C, Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place Larger phase angle is all kept, the feature of viscous liquid is shown.The phase angle of Lutrol F127 gel in place with angular frequency increase And increase, the phase angle of nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place then reduces with the increase of angular frequency (Fig. 2A-Fig. 2 B), the characteristic with shear shinning.At 34 DEG C, Lutrol F127 gel in place and nanometer hydroxyapatite- The phase angle of PGE2-PLGA-MSs hydridization gel in place is smaller, and phase angle reduces with the increase of angular frequency (see Fig. 2A-figure 2B), the rheological properties of typical gel are shown.
3, the plural number of Lutrol F127 gel in place and nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place Viscosity and angular frequency (rad.s-1) between functional relation (see Fig. 3).
Rheology characteristic test result is shown：At 15 DEG C or 34 DEG C, the gel containing nanometer hydroxyapatite is shown as The slightly increase of viscosity；Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place has typical temperature-responsive reverse The feature of gelling is in the solution state of high fluidity at a lower temperature, and temperature is formed after increasing with some strength Gel (see Fig. 4 A- Fig. 4 D).
The result shows that nanometer hydroxyapatite and PGE2-PLGA-MSs can in poloxamer188 solution hydridization, 25 DEG C or more become gel be used in body local sustained release medication.

Claims (2)

1. a kind of nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place, which is characterized in that according to parts by weight, receive Rice hydroxyapatite：0.3~1 part, PGE2-PLGA-MSs：0.005~0.02 part, Lutrol F127：0.5~5 part, water：5~ 15 parts；
The preparation method of the nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place, takes the Lutrol of formula ratio F127 spreads in water by several times, stirs to being uniformly dispersed, be placed in refrigerator and refrigerate 12~24 hours, nanometer hydroxyapatite is added, Ice bath, it is uniform using ultrasonic probe progress ultrasonic disperse, PGE2-PLGA-MSs is added, stirs evenly, stands, forms nanometer hydroxyl Base apatite-PGE2-PLGA-MSs hydridization gel in place, room temperature preservation；
Nanometer hydroxyapatite and PGE2-PLGA-MSs are entrained in the concentrated solution of Lutrol F127, utilize its reverse temperature The feature of sensitivity gelling：It is mobility liquid under low temperature, increasing the temperature to 25 DEG C, the above are gel, at room temperature low-viscosity injections Administration, is locally changed into gel in injection site, extends active constituent in the effect of periodontal local retention time to realize.
2. nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place described in accordance with the claim 1, which is characterized in that According to parts by weight, nanometer hydroxyapatite：0.5 part, PGE2-PLGA-MSs：0.01 part, Lutrol F127：2 parts, water：8 Part.
CN201510940200.XA 2015-12-16 2015-12-16 Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place and preparation method thereof Active CN105496943B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
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

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WO2014159863A1 (en) * 2013-03-14 2014-10-02 Genzyme Corporation Thermo-sensitive bone growth compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
The effect of nitric oxide on the production of prostaglandin E2 by hydroxyapatite-stimulated a human osteoblast (HOS) cell line;Erwan Sugiatno等;《Biomedicine & Pharmacotherapy》;20060324;第60卷;第147-151页 *
前列腺素E2缓释微球对成骨样细胞株MC3T3-E1生物学性能的影响;白艳洁等;《中国美容整形外科杂志》;20150430;第26卷(第4期);第235-238页 *

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