CN108096296A - Microencapsulation powder and acid gel based on spinach extract, which extend, generates nitric oxide production system and articles for use - Google Patents
Microencapsulation powder and acid gel based on spinach extract, which extend, generates nitric oxide production system and articles for use Download PDFInfo
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- CN108096296A CN108096296A CN201710942743.4A CN201710942743A CN108096296A CN 108096296 A CN108096296 A CN 108096296A CN 201710942743 A CN201710942743 A CN 201710942743A CN 108096296 A CN108096296 A CN 108096296A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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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
- A61K47/30—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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- 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
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
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Abstract
The present invention relates to a kind of nitric oxide production delay release system and complete set of supplies, spinach extract and acid gel including microencapsulation, spinach extract extract as nitric oxide donors, and there is acid gel enough acidity spinach extract is converted into nitric oxide.The nitric oxide production delay release system and complete set of supplies of the present invention is capable of the release NO of long-term, to can be long lasting for acting by site of action.
Description
Technical field
The invention belongs to field of medicaments, and in particular to one kind contains spinach extract microencapsulated insecticide as active component
Agent, system and articles for use containing the spinach extract microencapsulation medicament.
Background technology
In mammals, NO is a kind of in many physiology courses of nervous system, immune system and cardiovascular system
Endogenic Physiological effect substance, effect include vascular smooth muscle relaxation, and the vasodilation and blood flow for causing artery increase.NO
It is a kind of neurotransmitter, the activity and various functions with neuron are related, erect from avoidance learning to male and female genitals
(Kim et al.,J.Nutrition 134(2004)2873S).Also there is NO part to adjust macrophage to microorganism and swell
The cytotoxic effect of oncocyte.NO further relates to infectious shock, hypertension, apoplexy in addition to mediating normal physiological function
The different pathological and physiological condition with nerve degenerative diseases etc..
NO is applied in a variety of manners pharmacologically, and topical application NO can help the wound healing of wound and burn, hair
It grows, impotence and cause blood vessel dilatation in the place of needs (for example, promoting what is be damaged due to diabetes or other conditions
The circulation of patient peripheral's blood flow and the maturation in pregnancy period cervix).However, although NO is in itself with physiological activity,
It is in air or in vivo chemically unstable.Therefore, its pharmacology action is almost always through difference in the prior art
Various individually stable precursor compounds chemical reaction and generate.It is supplied usually using organic and inorganic nitrate as NO
Body.In the range of topical application, it is desirable that the dosage of NO is low, persistent.Fungicide powerful as one NO, confrontation
It is effective that life, which is known as drug-fast bacterium,.In antibacterial and other topical application, it is necessary to extend NO and skin contact when
Between.In antibacterial applications, NO dose therapeutically effectives be it is seldom, only a few millionths (ppm) (see Ghaffari et al.,
14 (2006) 21-29 of Nitric Oxide Biology and Chemistry)), but the validity of NO depends on maintaining and skin
The time length (4 (2011) 458-465 of Ormerod et al., BMCResearch Notes) of skin contact.
Although exist in the prior art (patent application CN201310355902.2, CN201310356220.3) and use micro-capsule
Change nitrite and be acidified the nitric oxide production system and method for delay generation of hydrogel, however its NO donor used is nitrous
Hydrochlorate, and nitrite is generally there are certain toxicity, toxicity is very big particularly when dosage is big.In addition the delayed time system and operation
The application of method is dependent on one or the water of several activation volumes, and there are certain limitations in concrete operations.
The content of the invention
To solve the deficiencies in the prior art, the present invention provides a kind of microencapsulation powder and acidity based on spinach extract
Gel generates nitric oxide production system, which, as NO donors, derives from natural plants, ingredient day using spinach extract
So, potential hazard of the nitrite as NO donors to body is avoided.
It is generated the invention further relates to the microencapsulation powder based on spinach extract and acid gel nitric oxide production complete
Articles for use.
Extend the nitric oxide production system that generates the present invention provides a kind of, delay of the invention generates nitric oxide production system
System can ensure the sustained release of NO under the conditions of the long period, and easy to operate, have the effect of sustained release.
The invention further relates to extend to generate nitric oxide production complete set of supplies.
The system and complete set of supplies of the present invention, preparation process is simple, and the system has higher biological safety, can grow
Phase plays the physiological activity of NO.
Description of the drawings
Figure 1A is the sectional view of the pad of the mixture (reaction generation NO) in an embodiment containing microencapsulation reagent；
Figure 1B is the sectional view of a pad comprising the internal component for keeping particle appropriate location；
Fig. 1 C are the sectional views of the pad that absorbed layer includes microencapsulation reagent (reaction generates NO) in an embodiment；
Fig. 2 is the release process of microencapsulation spinach extract and acid gel NO in the solution, and it is small that release time continues 5
When；
Fig. 3 is the release process of microencapsulation spinach extract and the acid gel NO in paste, and it is small that release time continues 10
When more than；
Fig. 4 is the release process of microencapsulation sodium nitrite and the acid gel NO in paste, when release time 8 is small；
Fig. 5 is the release process of microencapsulation spinach extract and the acid gel NO in paste, and acid gel is also containing also
Former agent, release time continue 10 it is small when more than；
Reference numeral：
Particle 1, layer 2, layer 3, separation layer 4, absorbent material 5, impermeable stratum 6.
Specific embodiment
Hereinafter, embodiments of the present invention will be described.
The invention discloses a kind of nitric oxide production delay release systems, and spinach extract and acidity including microencapsulation coagulate
There is enough acidity spinach extract is converted into nitric oxide for glue, the acid gel.
The present invention is using spinach extract as the donor for generating pharmaceutically acceptable NO.The reaction principle root of the present invention
According to following reaction equation (1) as it can be seen that generating nitrous acid by nitrite and sour (HA) reaction.In aqueous solution during nitrous acid low temperature
In be stable, but at room temperature, it is readily decomposed to NO and NO2, as shown in reaction equation (2).
In reducing agent (such as ascorbic acid, dihydroxy ascorbic acid (Asc (OH)2)) in the presence of, NO2It is easily converted to
NO, such as shown in following reaction equation (3).
2HA+NaNO2→2HNO2+ 2NaA (1),
HA is that one kind can be organic acid or inorganic acid
2HNO2→NO+NO2+H2O (2),
Nitrous acid decomposes, and generates nitrogen dioxide
NO+NO2+H2O+Asc(OH)2→2NO+2H2O+AscO2(3),
Ascorbic acid reacts, and generates nitric oxide
The present invention is used as the donor of NO by spinach extract, reduces potential danger of the toxicity to human body of nitrite
Evil.
In one embodiment, the vitamin C in spinach is remained in the spinach extract, therefore the present invention's is
System and complete set of supplies can remain to discharge NO for a long time in the case where not adding reproducibility member condition.In spinach extract
Vitamin C can prevent or slow down the reducing power that oxidation of nitric oxide is nitrogen dioxide, and also have direct-reduction NO2For
The ability of NO, so that being mainly NO by the gas discharged in said composition.
In one embodiment, the spinach extract adjusts each extraction with acid and walks in spinach extraction process is used
Rapid pH value of solution 3~4, to ensure the extraction of the Victoria C from spinach and activity.
The spinach extract of the present invention can use the conventional method of this field to extract, extraction process adjust pH for 3~
4, to ensure the extraction of Victoria C therein and activity.
In one embodiment, the spinach extract is in spinach extraction process is used, the pH value of solution that adjusts
Acid is oxalic acid.
In one embodiment, the spinach extract nitrite is 5.017 × 10-3Mg/ml, nitrate
Content is 0.236mg/ml, and Victoria C content is 1.21 × 10-2mg/ml。
In one embodiment, microencapsulation carrier is a kind of polymer substrate.The reagent and matrix are placed in Asia together
In millimetre-sized structure (at least one measurement regulation is less than 1 millimeter).This structure can be particle, fiber or film.
In an embodiment of the invention, connect using the spinach extract of microencapsulation and the acidifying hydrogel of sufficient acidity
It touches, conversion nitrite is nitric oxide.Although inorganic acid such as boric acid, it is also possible to which suitable, preferred acidulant uses
Organic acid, such as citric acid.Other acidulants can also include lactic acid, glyceric acid, formic acid, ascorbic acid or those this technology lead
Other organic acids known to the technical staff in domain.Inorganic acid that is biologically acceptable, having appropriate pKa value can also be used
(boric acid as escribed above).Gelling agent includes hydroxymethyl cellulose, hydroxyethyl cellulose, gelatin, agar, natural gum, starch
With the substances such as pectin.
The medium of dissolving acid can be aqueous medium or non-aqueous media.It is preferred that aqueous medium, easily prepares gel.Acid gel combines
Object can be in addition containing conjugate base sour used in one or more.Although preferred alkali is the conjugate base of the acid used,
Can be those other organic bases or inorganic base known to those skilled in the art.Embodiments of the present invention can be direct
Applied to cycling, the quickening wound healing for promoting skin, a period of time is kept on scalp as a kind for the treatment of to promote hair
Growth, and the beneficial positions of other local release NO can be used in.
It is nitric oxide production further to assist in keeping comprising reducing agent in gel in an embodiment of the invention
Bioactivity.Acidulant can also be reducing agent, such as ascorbic acid (vitamin C) or ascorbic acid derivates.The Vitamin C
Acid derivative includes but not limited to 3-O- ethylascorbyls and other 3- alkyl ascorbic acids, 6-O- caprylyls-Vitamin C
Acid, 6-O- dodecanes acyl group-ascorbic acid, 6-O- tetradecanes acyl group-ascorbic acid, 6-O- octadecanoyls-ascorbic acid and
6-O- decanedioyls-ascorbic acid.Preferably reducing agent has and is prevented together with the Victoria C in spinach extract or slow down nitric oxide
The reducing power of nitrogen dioxide is oxidized to, and also there is direct-reduction NO2For the ability of NO, so that by being released in said composition
The gas put is mainly NO.Preferred reducing agent includes ascorbic acid, ascorbic acid derivates, the salt of ascorbic acid, tocopherol,
Arabo-ascorbic acid or alpha-tocopherol.
An embodiment of the invention discloses a kind of gel of acidifying of suit and the spinach extract of microencapsulation.Acid
The gel of change and the spinach extract of microencapsulation are individually wrapped in damp-prrof packing, before application mixture, open bag
Dress, their content is mixed immediately.In another alternate embodiment, the spinach extraction of microencapsulation
Object and acidulant are wrapped damp-prrof packing together or individually.Before application, packaging is opened, it is aqueous with quantitative water or neutral pH
Gel mixes their content.
A kind of production method of micro-capsule：A kind of lysate of reagent or polymer solution spraying are dried, generate tiny point
The powder of scattered single particle (inside includes the reagent being dispersed in polymer substrate).The making of other micro-capsules can also be used
Method, such as pan coating, air suspension coating, centrifugation extruding, fibre spinning, fiber extrusion, nozzle vibration, ionic gelation,
Coacervation phase separation method, interface-cross-linked, situ aggregation method and matrix polymerisations.
A kind of embodiment prepared by the spinach extract of the microencapsulation of the present invention can add steady in spinach extract
Determine agent, stabilizer can maintain ascorbic activity therein, stabilizer over a long time in micro-capsule preparation process and in storage
Can be L-cysteine hydrochioride and sodium pyrosulfite.
In order to be suitable for medical indication, encapsulation polymer disclosed herein is the polymer of bio-compatible.Suitable is poly-
Closing object, (one kind is sent out in some grasses such as corn and cereal including ethyl cellulose, natural polymer such as zein
The molten seed storage protein of existing alcohol), chitosan, hyaluronic acid, alginic acid, biodegradable polyester, polyanhydride, polyethylene
(ortho esters), polyphosphazene or polysaccharide (see 10 (2005) 146-161 of Park et al., Molecules).
The composition of reagent microencapsulation described above is used in pharmaceutical agent conveying and is well-known.See Shalaby
and Jamiolkowski,US Pat.No.4,130,639；Buchholz and Meduski,US Pat.No.6,491,
948.However, in all these compositions, the reagent of microencapsulation be therapeutic agent in itself, therapeutic agent is not the examination by microencapsulation
What the reaction of agent generated.The nitric oxide releasing polymer for being related to nitric oxide adduct/donor existing in medical literature is retouched
It states, for example, Arnold, US Pat.No.7,829,553 (diazeniumdiolate is carbon-based to be attached on hydrophobic polymer)；Knapp,
US Pat.No.7,135,189 (precursor and nitric oxide donors of nitrosothiols).
The application of embodiment of the present invention include directly apply microencapsulated agents to wound, wound dressing, surgical dressing,
Protector on the bed of patients with bedsore (or may develop into patient), socks are suitble to other of diabetes and other dyshaemia patients
Clothes, orthopaedics gypsum and the NO local deliveries for vasodilator in the treatment of sexual dysfunction.The present invention can also meet
Medical supplies (such as intravascular stent, conduit, pacemaker, defibrillator, heart assistance dress with being conventionally implanted into or being inserted into body
Put, artificial valve, electrode and orthopaedic screw and pin) needs relevant, to a small amount of and lasting NO dosage.
The present invention can be a wound dressing bag or bandage bag, and a part for the wound dressing includes microencapsulation reagent
Particle.This part dressing has also combined a kind of material for having water retention property, to keep making particle required when being in wet environment
Suitable moisture.It soaks dressing and starts reagent reacting, dressing starts to discharge NO.Dressing is designed such that near wound and releases
Put NO.
An embodiment of the invention discloses a kind of delay release NO technologies that are multiduty, coming from delamination liner.
Cross section as shown in Figure 1A：Particle 1 is included between layer 2 and layer 3, and at least one in middle level 2 and layer 3 is body-facing layer
To transmit gaseous state NO, while at least one is outward-facing layer, this outward-facing layer has impermeable or moisture of withing a hook at the end
(liquid of application can be allowed to be transferred in particle and/or maintain particle to be in wet environment).It is desirable that the one side padded provides
In the application of NO, one of layer 2 or layer 3 are impermeable NO.Extract in the spinach that the particle of submillimeter level includes microencapsulation
Take object.In aqueous environment, it be combined with each other from the reagent of particle conversion formation and generates NO.When water is introduced in the pad,
Reagent starts to discharge, and NO starts to generate.
In embodiment as shown in Figure 1B, outer layer 2 and 3 is separated by a separation layer 4, and layer 4 is used to maintain outer layer
Spacing and keep particulate layer appropriate location.The agent particulates contained can be embedded into or be otherwise affixed to separation layer
On 4 or on the inner surface of any one in outer layer 2 or 3.
The pad of type as shown in Figure 1 can be prepared into any size and shape specified.Vertical dimension in Figure 1A-C
There is no a ratio, absorbent material 5 can it is thicker than the pad containing reagent very much.
There are many applications for such pad.They can by being placed on wound and cover a suitable bonding it is medical
Adhesive tape layer and simply use.They can also include ready-made bandage or dressing.Optionally, bandage or dressing are furnished with one
A parcel is small to include the microencapsulation reagent that react generation NO.In addition, reagent can be attached to different material layers, so
After fit together to form complete bandage or dressing.
The pad of other structures shown in Fig. 1 can be used as long-lasting antibacterial cleaning wiping cloth.This pad can adapt ruler
It is very little, it is inserted into the clothes such as socks or panty girdle of dyshaemia patient.By the gasket construction to edge of materials and comprising particle
Suitable treatments are carried out, pad can also be used as the fabric of the socks of dyshaemia patient, gloves and other clothes in itself.These clothes
Dress can be living by the Natural Water shunt excitation from patient skin or the moisture activation by addition.
Another embodiment of the invention is the layer pad shown in Fig. 1 C, the bed course by it is above-mentioned containing fine-grained pad,
Absorbed layer or permeable formation 5 and the impermeable stratum 6 below it form.This absorbed layer pad is suitable for or is starting to send out
Transform into the patient of bedsore.This kind of patient can generate suitable moisture by the urinary incontinence and sweat.Moisture generates the lining of NO by activating
Pad, and extra moisture can be padded following absorbed layer and be absorbed.Bedsore is washed in NO by such arrangement, nitric oxide
Bedsore is stimulated to heal, prevents the further expansion of ulcer area.
In different applications, low dose of NO be applied topically to penis so as to the telotism of rapid stimulation male rat
It is proved to be very effective (Han et al., Journal of Sexual Medicine 7 (2010) 224).It is of the invention public
The topical application of the NO of the similar effect for the mankind is opened.Side effect there are many systemic medications of sex dysfunction at present,
And need a period of time that can just come into force., it is necessary to this in terms of controllability and the systemic side effects without finding
Quick-acting, local treatment drug.Generate the drying coating that the reagent of NO can be placed in the dressing of erectile tissue.One implementation
Mode is used as the dressing of men's or female condom inside.The dressing that will be applied onto erectile tissue soaks to activate the examination
Agent, delay release NO.
Another embodiment of the invention, sheath inner surface scribble coating, and the coating includes the examination of microencapsulation
Agent, when in aqueous solution, microencapsulation reagent, which reacts to each other, generates NO.The particle size regimes of present embodiment can be 0.01
To 100 microns, preferred scope is Micron.Smaller particle size is conducive to be attached to table in sheath during prepares coating
Face, the time scale of NO releases is minute rather than hour.In using such embodiment, user is putting on sheath
An aquo-compound such as K-Y jellies (being produced by McNEIL-PPC, Inc., Ft.Washington, PA) are applied to before
On erectile tissue.When asperity contact to aquo-compound starts to discharge NO.The NO of release is limited in sheath until its quilt
Erectile tissue Transdermal absorption is to stimulate and prolonged erection.
Another embodiment of the invention is a kind of gel reagents suit of sexual arousal, gluey comprising a kind of similar K-Y
The aqueous gel compound packaging of object and a kind of damp-prrof packing of reagent containing microencapsulation, the reagent one react in aqueous solution
Generate NO.Before use, opening packaging mixing aqueous gel, applied to the external genital organs of male/female user, its blood is stimulated
Flowing, so as to promote penis and clitoral erection.Property of this suit available for the treatment of sexual dysfunction and raising male and female
Life satisfaction degree.
Although without the clinical research of the mankind, the research of rat is shown Seitz etc. (US Pat.No.6,103,
275) described gel combination can stimulate hair growth.It is well known that local vessel expansion medicine such as minoxidil can have
Effect alleviates the alopecia of the mankind and stimulates natural on-off cycles of hair growth, therefore lasting low dosage NO (NO is a kind of effective vasodilator)
Topical application is likely to have therapeutic effect to alopecia.Therefore, application of another disclosed herein delay release is to delay
It solves alopecia and stimulates the equipment and composition of hair restoration.One specific embodiment is made of material as shown in Figure 1
The cap of head shapes, for hair growth.Cap is fabricated to and is suitable for applying in the bareheaded region of patient head, is moistened with water
To activate it.
The invention will now be further described with reference to specific embodiments, and the advantages and features of the present invention will be with description more
To be clear.But these embodiments are only exemplary, do not form any restrictions to the scope of the present invention.Those skilled in the art
It should be understood that the details and form of technical solution of the present invention can be carried out without departing from the spirit and scope of the invention
Modifications or substitutions, but these modifications and replacement are each fallen in protection scope of the present invention.
Used chemical reagent is that analysis is pure in the embodiment of the present invention, purchased from Chinese medicines group.To make the present invention more
It is readily appreciated that with reference to specific embodiments the present invention is further explained.Experimental method of the present invention, if without special theory
It is bright, it is conventional method；If the biomaterial without specified otherwise, commercially obtains.
The preparation of 1 spinach extract of embodiment
The extraction of 1.1 spinach
The edible portion of spinach with tap water and deionized water is cleaned, is dried, is chopped into fritter, takes 10g, is put into big burning
In cup, add 50mL deionized waters, it is 3~4 to adjust extracting solution pH with oxalic acid, after grinding, is put into 70 DEG C of water-baths and is incubated 30min,
Extract liquor is filled into the volumetric flask of 100mL, and 100mL is settled to deionized water, and it is 3~4 to adjust extracting solution pH with oxalic acid, then
10mL or so is concentrated into, is transferred in the beaker of 250mL, adds in 5mL saturations borax soln and l00mL (70~80 DEG C) hot water,
It is 3~4 to adjust extracting solution pH with oxalic acid, is put in boiling water bath, heats 15min, and is constantly shaken, and room temperature is cooled to after taking-up, then is added
Enter l0mL potassium ferrocyanide solutions, l0mL acetic acid zinc solutions and 2g activity powdered carbons, after adding every time, then abundant mixing shifts
Into the capacity volumetric flask of 250mL, it is 3~4 to adjust extracting solution pH with oxalic acid, and with water constant volume, filtering obtains the molten of colorless clear
Liquid.
L-cysteine hydrochioride is further added in extraction process and sodium pyrosulfite can guarantee the Victoria C in extraction process
Activity, select L-cysteine hydrochioride content as 0.1%, pyrosulfurous acid sodium content is 0.2%.
The measure of 1.2 nitrate
With the content of Spinach By Spectrophotometry extract nitrite and nitrate, the results showed that, spinach extraction
Object nitrite is 5.017 × 10-3mg/ml；Nitrate content is 0.236mg/ml.
With the content of Victoria C in Spinach By Spectrophotometry extract, the results showed that, Victoria C content is in spinach extract
1.21×10-2mg/ml。
The preparation of 2 microencapsulation spinach extract of embodiment
Spinach extract prepared by embodiment 1 is concentrated, by being spray-dried by spinach extract, L-cysteine hydrochioride
It is prepared with the solution of sodium pyrosulfite (Victoria C stabilizer), zeins and volatile solvent composition with the molten egg of corn alcohol
The particle of the white spinach extract for matrix, contains the nitrite for being equivalent to 10% (weight percent).The molten egg of corn alcohol
It is the protein of the Pro-rich obtained from corn in vain, can be used for processed food and medicine as the matrix of coating and encapsulation
Product.It is classified as generally accepted safety (GRAS) by Food and Drug Administration (FDA).The solution is the 10% molten egg of corn alcohol
In vain (Flo Chemicals, 29 Puffer St., Ashburnham, MA 01430 (Lot F40000111C6)) be dispersed in by
Ethyl alcohol：Water (90:10) in the mixture of composition.Also containing stabilizer L-cysteine hydrochioride and sodium pyrosulfite (dimension in solution
C stabilizers), L-cysteine hydrochioride content is 0.1%, and pyrosulfurous acid sodium content is 0.2%, which is distributed to use
In the drier of spinning disk atomization device, particle diameter scope formed in this way is between 10 to 100 microns, these particles
The zeins matrix being dispersed therein comprising spinach extract.Zeins is insoluble in water, when particle is sudden and violent
When being exposed to water, water, which is diffused at leisure in zeins matrix, dissolves spinach extract Sodium Nitrite and Victoria C, contains Asia
The solution of sodium nitrate is diffused out from particle at leisure, so as to generate the sustained release of the sodium nitrite of long period.
The release of 3 microencapsulation spinach extract of embodiment and acid gel NO in the solution
The aqueous solution of 100 milliliters (100ml) is prepared, wherein PE9010 (a kind of anti-corrosions containing 5.6g citric acids and 0.3g
Agent is produced, 30 Two Bridges Road Suite 225, Fairfield, NJ 07004, USA by Sch ü and Mayr).
The solution of 40 milliliters (40ml) is positioned in beaker, is measured with the nitric oxide for the inNO-T for being equipped with amiNO-700 probes
NO concentration in system (Innovative Instruments, Inc., Tampa, FL 33637) detection solution.By 10 milligrams
(10mg) embodiment 2 prepare the spinach extract comprising zeins microencapsulation particle, at the appointed time zero when
(0) it is added in the solution, the NO contents in recording solution, the generation of NO generates after particle is added in, and at about 20 minutes, generates
NO formed from liquid, then NO is gradually increased, and peak value is about reached when 1 is small, is then gradually decreased.The release of entire NO
When time maintenance 5 is small, the NO comes from sour according to previous reaction in the sodium nitrite and solution distributed from microencapsulated particles
The reaction that formula (1)-(3) are occurred.The release process of NO is shown in Fig. 2.
The release of 4 microencapsulation spinach extract of embodiment NO in the solution
The particle 10 milligrams (10mg) prepared in embodiment 2 is placed in a container.Add this mixture to containing
In the beaker of 40 ml deionized waters, stir evenly.
Be equipped with amiNO-700 probes inNO-T nitric oxide measuring system (Innovative Instruments,
Inc., Tampa, FL 33637) NO concentration in detection solution, the probe tip of amino-700 at the appointed time zero when (0)
It is added in the solution, the NO contents in recording solution, next records NO signals, in the monitoring of first three hour, can examine
Go out faint NO.
The release of 5 microencapsulation spinach extract of embodiment and acid gel NO in paste
The present embodiment is intended to simulate the microencapsulation spinach extract of equivalent and acid gel when being applied directly to patient body-surface,
The release process of NO.
The 10 milligrams of particles that will be prepared in embodiment 2, being positioned over one has on the pan paper of wrinkling.Amino-700's
Probe tip is inserted into and is covered completely by mixture of powders.The acid gel prepared with the embodiment 3 of equivalent and microencapsulation spinach
Extract is uniformly mixed, next record NO signals, in recording process, can in due course be added according to paste system drying regime micro-
Measure deionized water, in the release of entire NO, begin from start recording, about 1 it is small when or so the release of NO reach relatively high water
It is flat, and process is entirely discharged for more than 10 hours.And the level of NO is constantly in stable and stable state during being somebody's turn to do.NO
Release process see Fig. 3.
The release of 6 microencapsulation sodium nitrite of embodiment and acid gel NO in paste
It is molten by sodium nitrite, ethyl cellulose and volatility by being spray-dried according to the microcapsule preparation method of embodiment 2
The solution of agent composition is prepared using ethyl cellulose as the particle (sodium nitrite weight ratio 10%) of the sodium nitrite of matrix.
By 10 milligrams of microencapsulation sodium nitrite particles of above-mentioned preparation, being positioned over one has on the pan paper of wrinkling.
The probe tip of amino-700 is inserted into and is covered completely by mixture of powders.With acid gel prepared by the embodiment 3 of equivalent with
Microencapsulation sodium nitrite is uniformly mixed, next record NO signals, in recording process, can be fitted according to paste system drying regime
The micro deionized waters of Shi Tianjia in the release of entire NO, begin from start recording, about 1 it is small when or so the release of NO reach opposite
Higher level, and entirely discharge process up to 8 it is small when.And the level of NO is constantly in stable and stable state during being somebody's turn to do.
Entire NO releases process is shown in Fig. 4.
The release of 7 microencapsulation spinach extract of embodiment and acid gel NO in paste, acid gel is also containing reduction
Agent
The present embodiment is intended to simulate the microencapsulation spinach extract of equivalent and acid gel when being applied directly to patient body-surface,
The release process of NO.Reducing agent Victoria C is also additionally added in the acid gel of preparation.
The aqueous solution of 100 milliliters (100ml) is prepared, wherein containing 5.6g citric acids, 2.2g ascorbic acid and 0.3g
PE9010 (a kind of preservative is produced, 30 Two Bridges Road Suite 225 by Sch ü and Mayr,
Fairfield,NJ 07004,USA)。
By 10 milligrams of particles, being positioned over one has on the pan paper of wrinkling.The probe tip insertion of amino-700 is simultaneously complete
It is covered entirely by mixture of powders.It is extracted with the acid gel containing additional reducing agent of the above-mentioned preparation of equivalent with microencapsulation spinach
Object is uniformly mixed, next record NO signals, in recording process, can add micro go in due course according to paste system drying regime
Ionized water in the release of entire NO, begins from start recording, and the release of about 40 minutes or so NO reaches relatively high level,
And process is entirely discharged for more than 10 hours.And the level of NO is constantly in stable and stable state during being somebody's turn to do.Entirely
NO releases process is shown in Fig. 5.
It is above-mentioned the experimental results showed that, microencapsulation spinach extract of the invention can be compared with microencapsulation nitrite (microencapsulation
Nitrite can maintain the release of the NO of 8 hours) there is the NO release times of longer time, even if not adding additionally in systems
Add reducing agent ingredient, the release of NO physiology effective concentrations, and NO during this can be also maintained during when 10 is small
Rate of release it is constant.
Analyze above-mentioned reason, it may be possible to the specific modality of nitrite and Victoria C in spinach extract or with there are other
Substance, which forms composite construction, can maintain the prolonged release process of NO.
The above is only the preferred embodiment of the present invention, and limitation in any form is not done to the present invention, though
So the present invention is disclosed above with preferred embodiment, however is not limited to the present invention, any to be familiar with this professional technology people
Member, in the range of technical solution of the present invention is not departed from, when the technology contents using the disclosure above make a little change or repair
The equivalent embodiment for equivalent variations is adornd, as long as being the content without departing from technical solution of the present invention, technology according to the invention is real
Any simple modification, equivalent change and modification that confrontation above example is made still falls within the scope of technical solution of the present invention
It is interior.
Claims (14)
1. a kind of nitric oxide production delay release system, spinach extract and acid gel including microencapsulation are described acid solidifying
There is glue enough acidity spinach extract is converted into nitric oxide.
2. nitric oxide production delay release system as described in claim 1, which is characterized in that contain in the spinach extract
Victoria C from spinach.
3. nitric oxide production delay release system as described in claim 1, which is characterized in that the acidity is by following organic acid
In one or more offers：Citric acid, lactic acid, glyceric acid, formic acid and ascorbic acid.
4. nitric oxide production delay release system as described in claim 1, which is characterized in that the acidity is provided by boric acid.
5. therapeutic nitric oxide production delay release system as described in claim 1, which is characterized in that the acid gel bag
Include the one or more of following polymers：Hydroxymethyl cellulose, hydroxyethyl cellulose, gelatin, agar, natural gum, starch and
Pectin.
6. therapeutic nitric oxide production delay release system as described in claim 1, which is characterized in that the acid gel bag
Containing a certain amount of polymer, the viscosity of the polymer solution is the viscous of the hydroxyethyl cellulose aqueous solution of 0.7-3.0% (w/v)
Degree.
7. therapeutic nitric oxide production delay release system as described in claim 1, which is characterized in that the acid gel is also
Including reducing agent, reducing agent includes ascorbic acid (vitamin C) or ascorbic acid derivates；The ascorbic acid derivates include
3-O- ethylascorbyls and 3- alkyl ascorbic acids, 6-O- caprylyls-ascorbic acid, 6-O- dodecanes acyl group-Vitamin C
Acid, 6-O- tetradecanes acyl group-ascorbic acid, 6-O- octadecanoyls-ascorbic acid and 6-O- decanedioyls-ascorbic acid.
8. therapeutic nitric oxide production delay release system as described in claim 1, which is characterized in that the spinach of the microencapsulation
The capsule material of dish extract is ethyl cellulose, zeins, chitosan, hyaluronic acid, alginic acid, biodegradable
Polyester, polyanhydride, polyethylene (ortho esters), polyphosphazene or polysaccharide.
9. a kind of therapeutic nitric oxide production complete set of supplies that delay release is provided for patient, the spinach extract including microencapsulation
And there is enough acidity spinach extract is converted into nitric oxide for acid gel, the acid gel；The microencapsulation
Spinach extract and acid gel are placed respectively.
10. complete set of supplies as claimed in claim 9, which is characterized in that the spinach extract of the microencapsulation is placed in wound and applies
On material or bandage, the acid gel is placed in other container.
11. complete set of supplies as claimed in claim 9, which is characterized in that the spinach extract of the microencapsulation is coated on safety
The inner surface of set, the acid gel are placed in other container.
12. the answering in the drug for promoting wound healing is prepared of the complete set of supplies as described in claim 9-10 any claims
With.
13. the answering in the drug for promoting hair replacement is prepared of the complete set of supplies as described in claim 9-10 any claims
With.
14. the complete set of supplies as described in claim 9 or 11 is preparing the application in overcoming the drug of sex dysfunction.
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| US5994444A (en) * | 1997-10-16 | 1999-11-30 | Medtronic, Inc. | Polymeric material that releases nitric oxide |
| US6103275A (en) * | 1998-06-10 | 2000-08-15 | Nitric Oxide Solutions | Systems and methods for topical treatment with nitric oxide |
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