CN107693490A - A kind of nanometer formulation and its composition of the glucosyl group modification for treating pulmonary hypertension morbidity - Google Patents
A kind of nanometer formulation and its composition of the glucosyl group modification for treating pulmonary hypertension morbidity Download PDFInfo
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- CN107693490A CN107693490A CN201711009361.2A CN201711009361A CN107693490A CN 107693490 A CN107693490 A CN 107693490A CN 201711009361 A CN201711009361 A CN 201711009361A CN 107693490 A CN107693490 A CN 107693490A
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- A61K9/10—Dispersions; Emulsions
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The present invention relates to a kind of nanometer formulation and its composition of the glucosyl group modification for treating pulmonary hypertension morbidity, including following component：Medicine, targeting glucosyl group, polyethylene glycol material and nanometer formulation, nanometer formulation is connected with targeting glucosyl group by polyethylene glycol material.In the nanometer formulation of the glucosyl group modification of the treatment pulmonary hypertension morbidity of the present invention, nanometer formulation can load water-soluble or insoluble drug, and have higher Drug loading capacity, can increase accumulation of the medicine in lesions position；The ability of stove position targeting is remarkably improved after the modification of glucose target base, improves therapeutic action.
Description
Technical field
The present invention relates to a kind of nanometer formulation for the glucosyl group modification for treating pulmonary hypertension morbidity, there is good targeting
Property, belong to novel nano targeted drug area research.
Background technology
Pulmonary hypertension (PAH) is the general name of a clinically major class pulmonary vascular disease, is increased with pulmonary vascular resistance, blood in situ
Bolt is formed, pulmonary artery remodeling is characterized.Clinical manifestation is expiratory dyspnea, cyanosis, spitting of blood, syncope, right heart insufficiency after activity.
The disease is once making a definite diagnosis, even if using current maximally effective therapeutic scheme, patient's death rate of 1 year is also up to 15%.Pulmonary hypertension
Patient's Pulmonary Vascular early stage pathology, which damages, is mainly shown as no flesh arteriole flesh, lung parteriole medial thickening around acinus, with
There is the Cong Yuan lung parteriole lesions of characteristic or sample lesion of gathering together in disease progression, vascular bifurcation position.They are Pulmonary Vasculars
Important step in pathological process, it can be in progress to types such as more serious lung arteriolar dilatation, necrotizing angitis, and by blood vessel
Proximate involves, and is the key point that can pulmonary artery remodeling reverse.In monocrotaline PAH models are combined in left pneumonectomy,
HIF-1 α are mainly in the high expression of propagation inner membrance, and the other positions of blood vessel, including the middle film thickened have no expression.HIF-1 α by with
Hypoxia responsible element (5 '-CGTG-3 ') combines in target gene promoter, and regulatory gene transcription promotes albumen synthesis, participates in blood
Pipe is formed, glycometabolism, the different physiological roles such as RBC acceptor garland rate.HIF-1 α take part in the expression of about 80% glycolysis key enzyme,
Wherein comprising glucose transporter (GLUTs), hexokinase -2 (HXK-2) up-regulated expression.Cell is by raising GLUTs and HXK-
2 accelerate the intake to glucose, to meet to energy requirement.Other researchs also indicate that GLUTs in monocrotaline pulmonary hypertension rat
The high expression of injury of pulmonary vessels site specific.Therefore the nanometer formulation of glucose aglucon modification is designed for target molecule based on GLUTs
It can realize that medicine conveys to the targeting at new intima, avoid damage of the medicine to other position endotheliums, improve the treatment of medicine
Effect.
The content of the invention
It is an object of the present invention to provide the nanometer formulation and its composition of a kind of glucosyl group modification, it is by following component institute
It is made：Medicine, glucosyl group, polyethylene glycol material and nanometer formulation.The method of administration of said preparation is intravenous injection, for treating
Pulmonary hypertension, the ability of stove position targeting is remarkably improved, improves therapeutic action.
Technical scheme is as follows：
The invention provides a kind of glucosyl group modification nanometer formulation and its composition, medicine, targeting glucosyl group,
Polyethylene glycol material and nanometer formulation, nanometer formulation is connected with targeting glucosyl group by polyethylene glycol material.
The nanometer formulation is selected from liposome, emulsion systems, nanocrystal, polymer micelle, nanometer (micro-) capsule (ball), nothing
The one or more of machine organic nano grain.
Described medicine is dichloroacetate (DCA), silaenafil, cyclosporine, prostacyclin, endothelin-receptor antagonists
One or more.
Described polyethylene glycol material is the PEG decorative materials of long-chain or short chain.
Described polyethylene glycol material is maleimide-polyethylene glycol-succinimide.
Described targeting glucosyl group be selected from can with glucose transporter (GLUTs) combine D-Glucose, phlorose,
β-glucose, gluconic acid, one in glucaric acid, glucuronic acid, fructose, lactose, mannose and other polyhydroxy aldehyde
Kind.
The present invention is to utilize polyethylene glycol functional material (DSPE-PEG2000-NH2) connect nanometer formulation and glucosyl group
Connect.Glucuronic acid is dissolved in methanol/pH 4.0PBS (80/20, v/v), adds EDCHCl and NHS, stirring.Then plus
Enter DSPE-PEG2000-NH2, continue to react.Product at reduced pressure methanol removed by evaporation, sediment centrifugation is lyophilized to produce DSPE-
PEG2000-glu。
The present invention finally provides the nanometer formulation of the glucosyl group modification and its different pharmaceutical composition is moved in lung
Application in the morbidity treatment of arteries and veins high pressure.
Beneficial effect：
In the nanometer formulation of the glucosyl group modification of the treatment pulmonary hypertension morbidity of the present invention, nanometer formulation can water load
Molten or insoluble drug, and there is higher Drug loading capacity, accumulation of the medicine in lesions position can be increased；Glucose target base is modified
The ability of stove position targeting is remarkably improved afterwards, improves therapeutic action.
Preparation-obtained nanometer formulation utilizes dynamic light scattering nanometer particle size instrument measure particle diameter, particle diameter in embodiment 1-5
Polydispersity coefficient and ZETA current potentials；Characterized using ESEM and transmission electron microscope.Nanometer formulation particle diameter produced by the present invention
Scope is 50-200nm, and current potential is about -25mv.
Brief description of the drawings
Fig. 1 is the grain size distribution that nanometer formulation is made in embodiment 1.
Fig. 2 is the transmission electron microscope picture that nanometer formulation is made in embodiment 1.
Fig. 3 is the In-vitro release curves that nanometer formulation is made in embodiment 1.
Fig. 4 is the entrapment efficiency that nanometer formulation is made in embodiment 1.
Embodiment
Embodiment 1
Prescription：
Preparation method：
S100, DSPE-PEG2000-glu, DOPE and cholesterol are dissolved in chloroform, vacuum decompression evaporation 2h removes molten
Agent.Adipose membrane is with 200mM ammonium sulfates aquation until adipose membrane all comes off.Thick liposome microjet 20000psi averages 5 are followed
Ring.The liposome of acquisition is dialysed 2h to 1000mL 0.9%NaCl, 2 times.Then liposome is preheated to 55 DEG C, the body such as addition
The long-pending 4mg/mL silaenafil solution containing 1.8%NaCl, 10min is incubated, completes to carry the preparation of silaenafil liposome.
Embodiment 2
Prescription：
Preparation method：
Take lecithin, DSPE-PEG2000-glu and medicine to be added in 5ml centrifuge tubes, add injection soybean oil and oleic acid
And ultrasonic dissolution.Glycerine and water for injection are taken, puts in 50ml beakers, stirs.Cyclosporine solution is added in the aqueous solution,
20,000rpm, which disperse at a high speed 30s, is made colostrum, and 500bar is high-pressure homogeneous again and circulates 15 times.
Embodiment 3
Prescription：
Preparation method：
DOPE, DSPE-PEG2000-glu, phosphatide (Lecithin S100), medicine and cholesterol is taken to be placed in eggplant-shape bottle,
Dissolved with dichloromethane and in slowly rotation forms uniform lipid membrane on Rotary Evaporators, bath temperature is 50 DEG C.Treat
The organic solvent of residual is removed after solvent volatilizes, in vacuum drying chamber.Contain being added with 0.05M pH7.4 PBS solution
In the eggplant-shape bottle of lipid film, add a little bead and help aquation, aquation 30min is so that lipid film fully comes off in 30 DEG C of water-baths
And aquation is complete, you can.
Embodiment 4
Prescription：
Preparation method：
Take Precirol ATO 5 and Captex100 to heat melting, add ciclosporin A stirring and dissolving, the oil phase of system；Will
DSPE-PEG2000-glu is dissolved in Tween-80 (5%, w/v) solution, and is heated to 80 degree, and aqueous phase is made；Oil phase is taken to add
Aqueous phase, 20000rpm is scattered at a high speed, high-pressure homogeneous 20 times of 500bar.
Embodiment 5
Prescription：
Preparation method：
Take Lecithin S100, Labrafac CC, Span 80 to put in 50mL beakers, dissolve by heating, add dichloroacetic acid
Sodium solution, 1000rpm stirring 20min, is made W/O colostrums；W/O colostrums are taken to add Tween-80 (5%, w/v) and DSPE-
In PEG2000-glu solution, 1000rpm stirring 20min, W/O/W colostrums are made；Finally, high-pressure homogeneous 10 times of 100bar.
Embodiment 6
Prescription：
Ciclosporin A 50mg
Amphiphilic macromolecular polymer 200mg
DSPE-PEG2000-glu 10mg
Preparation method：
Take amphiphilic macromolecular polymer, ciclosporin A, DSPE-PEG2000-glu to be placed in eggplant-shape bottle, use dichloromethane
Dissolve and in slowly rotation forms uniform film on Rotary Evaporators, bath temperature is 50 DEG C.After organic solvent volatilizes, very
The organic solvent of residual is removed in empty drying box.It will be added with 0.05M pH7.4 PBS solution in the eggplant-shape bottle containing film,
Add a little bead and help aquation, aquation 30min in 30 DEG C of water-baths.
It is described above, only it is presently preferred embodiments of the present invention, any formal limitation not is made to the present invention, it is any ripe
Professional and technical personnel is known, it is without departing from the scope of the present invention, real to more than according to the technical spirit of the present invention
Apply any simple modification, equivalent substitution that example made and improve etc., still fall within technical solution of the present invention protection domain it
It is interior.
Claims (8)
- A kind of 1. nanometer formulation for the glucosyl group modification for treating pulmonary hypertension morbidity, it is characterised in that：Including following component： Medicine, targeting glucosyl group, polyethylene glycol material and nanometer formulation, by polyethylene glycol material by nanometer formulation with targetting grape Glycosyl connects.
- 2. the nanometer formulation of the glucosyl group modification for the treatment of pulmonary hypertension morbidity according to claim 1, its feature exist In：The nanometer formulation is selected from liposome, emulsion systems, nanocrystal, polymer micelle, nanometer (micro-) capsule (ball), inorganic had The one or more of machine nanoparticle.
- 3. the nanometer formulation of the glucosyl group modification for the treatment of pulmonary hypertension morbidity according to claim 1, its feature exist In：Described medicine is dichloroacetate (DCA), silaenafil, cyclosporine, prostacyclin, the one of endothelin-receptor antagonists Kind is several.
- 4. the nanometer formulation of the glucosyl group modification for the treatment of pulmonary hypertension morbidity according to claim 1, its feature exist In：Described polyethylene glycol material is the PEG decorative materials of long-chain or short chain.
- 5. the nanometer formulation of the glucosyl group modification for the treatment of pulmonary hypertension morbidity according to claim 1, its feature exist In：Described polyethylene glycol material is maleimide-polyethylene glycol-succinimide.
- 6. the nanometer formulation of the glucosyl group modification for the treatment of pulmonary hypertension morbidity according to claim 1, its feature exist In：Described targeting glucosyl group is selected from D-Glucose, phlorose, the β-Portugal that can be combined with glucose transporter (GLUTs) Grape are sugared, gluconic acid, one kind in glucaric acid, glucuronic acid, fructose, lactose, mannose and other polyhydroxy aldehyde.
- 7. the nanometer formulation of the glucosyl group modification for the treatment of pulmonary hypertension morbidity according to claim 1, its feature exist In：The method of administration of preparation is intravenous injection, for treating pulmonary hypertension.
- 8. the nanometer formulation of the glucosyl group modification of the treatment pulmonary hypertension morbidity described in claim 1 is sent out in pulmonary hypertension Application in disease treatment.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711009361.2A CN107693490A (en) | 2017-10-25 | 2017-10-25 | A kind of nanometer formulation and its composition of the glucosyl group modification for treating pulmonary hypertension morbidity |
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| CN201711009361.2A CN107693490A (en) | 2017-10-25 | 2017-10-25 | A kind of nanometer formulation and its composition of the glucosyl group modification for treating pulmonary hypertension morbidity |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020177290A1 (en) * | 2019-03-04 | 2020-09-10 | 中国药科大学 | Pharmaceutical composition, preparation method therefor and use thereof |
| CN112220778A (en) * | 2020-10-16 | 2021-01-15 | 中国药科大学 | Combined delivery system for pulmonary hypertension treatment and preparation method thereof |
| CN112755005A (en) * | 2019-11-04 | 2021-05-07 | 四川大学 | Oral nano drug delivery system mediated by small molecular nutrient substances |
| CN115364055A (en) * | 2022-07-25 | 2022-11-22 | 中山大学附属第三医院 | Nitric oxide and drug loaded microvesicle and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020177290A1 (en) * | 2019-03-04 | 2020-09-10 | 中国药科大学 | Pharmaceutical composition, preparation method therefor and use thereof |
| CN112755005A (en) * | 2019-11-04 | 2021-05-07 | 四川大学 | Oral nano drug delivery system mediated by small molecular nutrient substances |
| CN112220778A (en) * | 2020-10-16 | 2021-01-15 | 中国药科大学 | Combined delivery system for pulmonary hypertension treatment and preparation method thereof |
| CN115364055A (en) * | 2022-07-25 | 2022-11-22 | 中山大学附属第三医院 | Nitric oxide and drug loaded microvesicle and preparation method thereof |
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Application publication date: 20180216 |