CN1246369A - Tissue humidifying composite and method - Google Patents

Tissue humidifying composite and method Download PDF

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CN1246369A
CN1246369A CN98117463A CN98117463A CN1246369A CN 1246369 A CN1246369 A CN 1246369A CN 98117463 A CN98117463 A CN 98117463A CN 98117463 A CN98117463 A CN 98117463A CN 1246369 A CN1246369 A CN 1246369A
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polymer
humidification
compositions
bioadhesive
water
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威廉姆·J·波罗纳
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Abstract

A composition and method for moistening epithelial tissue contains water, particular bioadhesive and preferable thickening agent. The method for preparing said composition is disclosed.

Description

Tissue humidifying composite and method
The present invention relates to be used to increase the compositions and the method for epithelial cell humidity, and especially comprise water, specific biological adhesive and preferably include the method and composition that is used for humidification of thickening agent.The present invention also relates to prepare the method for humidifying composite.
Some environment and pathologic condition cause the dry or dehydration of body of mammals membrane tissue.These conditions cause xerostomia (xerostomia), eye to do (dry symptom sicca condition) and vagina drying, dryness in the nasal cavity or mucous membrane of rectum drying and/or xerosis cutis, and this causes aesthetic indecency and/or uncomfortable to having knowing from experience of this symptom.
A kind of method that is used for making dry tissue humidifying has used oily matter as the main component in the emulsifiable paste, washing liquid, gel or the ointment that are applied to illing tissue in the trial that prevents to organize further dehydration.They work by covering fluid-tight hydrophobic barrier at tissue to be treated.Vaseline, mineral oil, lanoline and isopropyl myristate are the examples of used hydrophobic substance.These goods are limited to long purposes.In addition, they cause oiliness, the stickiness feeling of skin and the clothes that dyes.
The another kind of method that is used for humidification is used the hydrophilic molecules that can absorb water.Such as the hydrophilic micromolecule of glycerol and glycerin/water mixture, carbamide and propylene glycol is useful known wetting agent in skin moisturizing allegedly.
Adhering to several synthetic hydrophilic substance on skin and/or the mucosa when water exists has been used alone under various pathological conditions or has united use with one or more activity or therapeutic agent, but they are not as epithelial cell, as the exsiccant humidizer of the epithelial cell of skin or mucosa.These hydrophilic substances often are called hydrogel in this area.
More known hydrophilic, carboxyl functional polymers are promptly contained the carrier of those polymer of hydroxy-acid group as therapeutic agent.The U.S. 4,615,697 disclose and have been used for the preferred polymer polycarbophil that this invention is used with therapeutic agent.U.S. Patent number 3,074, the aquogel polymer carrier in 852 be it is said U.S. Patent number 2,798,053 polymer.The cross linked polymer of illustrative be it is said CARBOPOL 934.U.S. Patent number 3,074, interested especially polymer be it is said acid form in 852, and at U.S. Patent number 2,909, has carried out describing more specifically in 462.Its specifically described polymer it is reported it also is that B.F.Goodrich chemical company is with CARBOPOL 934 materials of selling.
U.S. Patent number 4,226,848 disclose the compositions that is used for pharmaceutical preparation is adhered to oral cavity or nasal membrane.Wherein the acrylate copolymer of disclosed illustrative is can be from B.F.Goodrich chemical company with trade mark CARBOPOL 934 lightly crosslinked acrylic acid-allyl sucrose copolymers of having bought it is said that it forms the tremelloid dispersion of high viscosity in water.
U.S. Patent number 4,548,990 disclose the drug delivery composition of sustained release, and its crosslinked polymer moieties prepares from comprising that 55%-99% water-insoluble monoene belongs to (monoolefinic) monomeric monomer or the mixture.This polymer allegedly expands in the second alcohol and water and expansion ratio is 2: 1～22: 1.
The European Patent Application No. 88112198.2 of useful especially polymerization of carboxylic acid copolymer in B.F.Goodrich company used in treatment or makeup, be described in the publication number 0301532, preferred US4,615,697 polymer and may comprise Carbopol 976.Fluffy, powdered acrylate copolymer prepares in the polymerisation medium such as carbon dioxide of anhydrous, organic solvent-free.The weight of this polymer about 0.1～6% is crosslinked.This copolymer is water-fast but inflatable in water on substantially.0.2% weight is scattered in and allegedly has the mucus viscosity in 1000 weeks of per second (" cps ") at least in the distilled water.
Hydrophilic, the carboxyl-functional water-soluble polymer has been used for cosmetic product.U.S. Patent number 4,863,725 disclose the copolymer of water miscible glycerol and methacrylic acid.Germany Offenlegungsschrift 24 19 046 has described the linear and crosslinked polymer that contains carboxyl and aldehyde radical as cosmetic composition.The open 61-72706 of Japan Patent relates to cross linked polyacrylate list-or two-hydroxypropyl acrylate polymer.PCT application number PCT/US89/00451, on August 10th, 1989, disclosed international publication number WO 89/06964 related to the polycarboxylic acids eye goods of the specific pH, viscosity and the osmolarity that are used for ophthalmic composition.
The hydroexpansivity of neither one instruction or suggestion such as polycarbophil or similar polymer in the publication of this area previously discussed but water-fast crosslinked bioadhesive polymer polycarboxylic acid polymer particularly can be used as under acid pH and are used for dry epithelial cell, as the humidizer in the epithelial compositions of hereinafter disclosed skin and mucosa.Yet PCT/US 89/00451 relates to the dry eye/tear that comprises Carbopol 976 soluble in water really substitutes goods.
The present invention includes the compositions and the method that are used to increase epithelial cell humidity.According to this method, epithelial cell contacts with the moisture humidifying composite of effective amount of humidification, and said composition contains the hydroexpansivity of water, amount of humidification but water-fast crosslinked bioadhesive polymer polycarboxylic acid polymer and preferred contains the level and smooth thickening agent of measuring of thickening.The bioadhesive polymer polymer is a hydroexpansivity but water-fast, graininess or fibrous crosslinked carboxyl functional polymer.This polymer is used to contact mammal such as people's epithelial cell.
The bioadhesive polymer polymer preferably contains (a) at least about 80%, preferably contain at least one carboxyl functional group at least about many recurring units of 90%, (b) according to unpolymerized initial substance weight, about 0.01% to about 6% of essentially no polyalkenyl polyethers, preferred about 0.01% to about 2%, more preferably from about 0.05% to about 1.5%, and 0.05% to about 1.0% cross-linking agent most preferably from about; That is, recurring unit and coupling agent.Thickening agent is water-dispersion type and preferred water dissolubility, nonionic or anionic polymer.
The bioadhesive polymer polymer is a water-insoluble but water-swollen.Opposite with the water-soluble polymer that can absorb in water above 100 times of its weight, the polymer of neither water-soluble (water-soluble less than 1%) generally can absorb about 40% to about 100% of its weight in water.
In preferred practice, exsiccant bioadhesive polymer polymer carries out magnitude classification by the 400 mesh sieves screening in the Unite States Standard sieve series.The diluent that the bioadhesive polymer granule can tolerate on physiology, and special in comprising the liquid of water, the dispersion also be preferred.This solution also can comprise other composition in the liquid that becomes known for being administered to epithelium.
The invention provides some advantages and benefits.
An advantage of the present invention is that its compositions does not stimulate the mucosa of its contact is significant.
Another advantage of the present invention is that bioadhesive polymer humidification polymer has and is beneficial to the obvious acid ph value of keeping the surface texture acid ph value and quite high buffer capacity.
Since the insolubility of bioadhesive polymer polymer, the sustainable long duration of humidification effect of the present composition, for example 2～3 days.
Another benefit of the present invention is that its compositions is relatively easily prepared.
According to following detailed, embodiment and claim, further benefit of the present invention and advantage are to it will be readily apparent to those skilled in the art that.
In the accompanying drawing that forms this description part
Fig. 1 display update commercial available is used to measure the side of the surface tensiometer of bioadhesive polymer adhesion strength and sees.
Fig. 2 for show be used to split with 0.3% weight have 3 of 1.56 gram/cubic centimetres (g/cc) density, 4-sodium catchol disulfonate, active force (dyne * 10 of the acrylic acid bioadhesive polymer polymeric reaction products of 5-hexadiene combined polymerization -2/ cm 2) to pH value figure; With
Fig. 3 be viscosity (for convenience, in cps, n is 10,000-100,000 is shown as 1-10 * 10 4) to shearing ratio (humidifying composite of 2 independent preparations of preparation described in the embodiment 4 is pressed in the n representative in rpm) figure.The result presses described in the embodiment 6 with Haake ROTOVISCO type RV-12 viscometer and obtains, and a kind of data of compositions show with solid garden, and the data of another kind of compositions show with hollow garden.
The present invention relates to by using humidifying composite to host mammal humidification such as mouth (mouth The chamber), epithelial composition and the method in the mucous membrane districts such as eye, vagina. Said composition is originally as containing Water composition, comprise the bioadhesive polymer of humidification effective dose and preferably include water-soluble or water dispersible poly-Close thickener. The difference of they and U.S. Patent number 4,615,697 and PCT/US89/00451 is it Lack the therapeutic agent that is different from such as the relative inertness liquid of water, and be mainly used in dry strip of tissue Part.
Bioadhesive polymer of the present invention is preferably water-insoluble but is water-swollen. Used herein The term water-insoluble meaning is that this bioadhesive polymer (lacking water-soluble impurity) is at its about pH 3～5 Acid form the time, under the concentration that is no more than about 2～3% weight, demonstrate do not have appreciable Viscosity. The term hydroexpansivity meaning is these goods, although be water-insoluble, what absorption can the amount of perceiveing Water is generally its about 60～100 times weight.
The design humidifying composite is used for epithelial cell, i.e. mammiferous skin and mucous membrane (mucous membrane), Such as horse or people's mucous membrane, in the presence of enough water gagings, said composition adheres on the mucous membrane with the life of expanding The thing adhesive. The composition that adheres to like this epithelium increases in the quite a long time and contacts The moisture of body part. This time is longer than the similar combination that does not comprise bioadhesive polymer disclosed herein The humidification time of thing. Really, for the humidification epithelial cell, this bioadhesive polymer can be 10～about 20 Hour, that is, maintain suitable position in the update time of mucous membrane or tissue to about 2～3 days time Put and keep active.
Useful composition is to being applied to wherein or animal on it is nontoxic basically in the present invention .
For time expand, method utilization maintenance of the present invention contacts with host mammal epithelium zone The hydrogel composition of a large amount of moisture content. This composition also serves as in addition polyelectrolye and restriction connects The ion of the mucous membrane that touches flows out. This ion with the water connection flows out and can cause water to flow out from tissue. This Outward, when being expanded by water-bearing media, this humidification bioadhesive polymer itself is exactly polyeletrolyte, and produces Give birth to the Donnan balance effect, cause promoting that ion flows into the tissue that contacts. Because cross-linked polymer is very big Bioadhesion and mucoadhesive properties, said composition keeps contacting with epithelial tissue the longer time.
Humidifying method of the present invention is for increasing " drying " tissue such as dry eyes, and dry skin is done Dry vagina, dry nasal meatus, the moisture in dry rectum road and dry oral cavity are effective.
According to this humidifying method,, contain the aqueous dispersion polymers thickening agent of the level and smooth amount of thickening by the aforementioned humidizer that contains water, humidification effective dose and preferred that provides.
In the presence of the enough water of expansion bioadhesive polymer, contact and make the compositions that contains bioadhesive polymer adhere to the zone that is contacted.If necessary, this contact is kept is enough to increase the epithelial cell that contacted and the time of adjacent tissue moisture.
The inventive method has reduced partial pH value.For example, the experimenter accepted the commercial vagina humidizer treatment of the present composition or other inanimate object adhesive agent every day after 5 days, in the women who accepts these two kinds of products, had noticed about 0.5 pH unit or more vagina pH value difference.Observe and use the woman vagina pH value of product of the present invention to be about 4.8, have the pH value that reduces than about value of being untreated of 5.6, kept after the treatment about 48 hours.
Common yeast, fungus and other microorganism that causes vaginal infection can not be grown well at pH 5 or when lower.Therefore, aforesaid humidifying method also provides the method that suppresses vagina yeast and fungal infection.
Every kind of compositions hereinafter described can be used according to this method.
Compositions of the present invention can be used to provide epithelial cell to contact with necessity between the compositions by some instruments.For example, can use said composition by said composition being clipped the zone for the treatment of humidification.Said composition can be used by aerosol apparatus, hands, tweezers, thromboembolism, plunger, irrigator or other suitable instrument.Contact conjunctival epithelium if desired, Aquo-composition hereinafter described can be splashed at the moment in the bag of angle.Contact the oral cavity if desired, nose, anus and/or vagina epithelium can be used by aerosol apparatus, hands, tweezers, thromboembolism, irrigator or other suitable instrument.
Compositions is put in position (keeping in touch) sufficiently long time so that the humidification in the zone of (treatment) that contacts is taken place and therefore provide its cosmetic effect to mammal.In most applications, the compositions of using is by the physical mechanism of nature, as the dispersion that causes by mechanicalness or corrosion or by aqueous body fluids such as vaginal secretions, or removes from health by flushing.The compositions that contains bioadhesive polymer humidification polymer also can be by the mechanism in the contact site, as losing by the tongue effect in epibulbar eyelid or the oral cavity.For mucosa, bioadhesive polymer humidification polymer adhere to the mucin of coverlay or film originally on one's body.Mucin is in about 10～20 hours, and per approximately usually 17 hours with regard to replaced (renewal), and adherent bioadhesive polymer humidification polymer can be lost with mucin.
The main component of humidifying composite of the present invention is the bioadhesive polymer polymer.
Active humidizer comprises bioadhesive polymer polymer, water and preferably includes the water-dispersion type thickening agent.Can there be adjuvant or diluent, and become known for other composition in the humidifying composite.
This bioadhesive polymer polymer comprises hydroexpansivity but is water-fast, the crosslinked carboxyl functional polymer of graininess or fibrous and the bioadhesive that shows hereinafter to be discussed.This polymer preferably contains (a) and contains at least one carboxyl functional group and (b) about 0.01%～6% at least about many recurring units of 80%, preferred about 0.01%～2%, more preferably from about 0.05%～1.5% cross-linking agent and essentially no polyalkenyl polyethers, percentage ratio are respectively according to the weight of unpolymerized recurring unit and cross-linking agent.Preferably, contain at least one carboxyl functional group, more preferably contain at least one carboxyl functional group at least about 95% recurring unit at least about 90% recurring unit.In great majority were preferably put into practice, this bioadhesive polymer contained the polymeric cross-linker of 0.05%～2% weight of having an appointment equally.
Bioadhesive polymer can be broadly defined as the material that adheres on biological surface alive or that newly kill such as mucosa or the skin histology." bioadhesive polymer " that this paper is used to define useful bioadhesive polymer humidification polymer is by at U.S. Patent number 4,615, method hereinafter described among 697 embodiment 2 is analyzed, and this method is measured and separated the rabbit gastric tissue necessary forces that adheres to 2 layers of new excision together by adhesive agent.
According to the method for embodiment 2, with the method in the U.S. Patent number 4,615,697, bioadhesive polymer may be defined as need be at least about 50 dyne/cm 2Active force with the material of the rabbit gastric tissue that separates 2 adhesions, new excision.More preferably be that this active force is at least about 380 dyne/cm 2Observed mean effort to polycarbophil is about 1073 dyne/cm 2The rabbit gastric tissue necessary forces upper limit of also not knowing to separate new excision at present, but it is believed that at least about 2000 dyne/cm 2
As previously mentioned, in order in insoluble polymer, to reach the hydroexpansivity amount of aequum, preferably contain at least one carboxyl functional group at least about the recurring unit of 80% preferred bioadhesive polymer.Provide the monomer of these recurring units to comprise undersaturated monoene and comprise acrylic acid, methacrylic acid, Fumaric acid, maleic acid, maleic anhydride that in polymerization process or afterwards hydrolyzable becomes its acid form, methylene succinic acid .beta.-methylacrylic acid etc.In these acid each can use separately or with other the acid of this class with one or more these sour medicine on or make up and go up acceptable salt and unite use.Acrylic acid is particularly preferredly to be used to provide the bioadhesive polymer polymer to contain the monomer of carboxyl recurring unit.
Being used for preferred bioadhesive polymer polymer of the present invention comes crosslinked by cross-linking agent known in the art.The preferred essentially no polyalkenyl polyethers of cross-linking agent, and especially preferably do not have the polyalkenyl polyethers, be present in CARBOPOL as report On average contain the polypropylene-base sucrose or the polypropylene-base tetramethylolmethane of 3 acrylic of per molecule at least in 934.Useful cross-linking agent example has divinylbenzene, N, N-diallyl acrylamide, 3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5 hexadiene etc.
The crosslinked amount of bioadhesive polymer also has certain importance.When the suitable crosslinking agent less than about 0.05% weight existed, this bioadhesive polymer became water solublity or water dispersible easily, thereby lost it to the important required water-insoluble of the present invention, hydroexpansivity feature.For the hexadiene cross-linking agent of divinylbenzene or dihydroxy or dimethyl replacement, according to the difference of polymer, when existing greater than about 1% or 2% cross-linking agent, the water swelliong power of bioadhesive polymer begins to occur appreciable decline.Preferably, this cross-linking agent exists with about 0.05%～1% or 2%.Yet preferred range will change with the character of polymer, the character of cross-linking agent and crosslinked degree especially.The amount of cross-linking agent refers to the percent of those precursors, unconverted monomer in the polymeric reactant mixture of bioadhesive polymer.
Therefore, bioadhesive polymer polymer used herein can partly be defined as the copolymerization product at least about the no polyalkenyl polyether crosslinking agent of the unsaturated monoene carboxyl-functional monomer of 80% weight and about 0.01%～2.0% weight.Can exist to constitute monomeric other monomer of 100% weight and be described below.
Except 2 kinds of top compositions, this bioadhesive polymer polymer also can comprise the C of polymeric unsaturated monoene recurring unit such as one or more above-mentioned acid 1-C 6The alkane ester is as ethylhexyl acrylate, butyl isobutene. ester and methylcrotonic acid ester; Average per molecule contains the hydroxyl alkenyl-sense ester such as the hydroxyethyl methacrylic ester of the above-mentioned acid that contains 2～3 carbon atom oxygen alkenyls of having an appointment 1～4, hydroxypropyl acrylate and 5 tetrem allyl diglycol mono acrylic esters; MAAm, acrylamide and their C 1-C 4Single-and two-alkyl derivative such as N methacrylamide, N-butyl MAAm and N,N-DMAA; Styrene; Deng, they are known in this area, can with above-mentioned monomer and the cross-linking agent combined polymerization that contains carboxyl functional group.The bioadhesive polymer polymer most preferably only never prepares in saturated mono thiazolinyl carboxyl functional group monomer and the cross-linking agent.
Bioadhesive polymer polymer used herein can be prepared by the described conventional polymerization technique of document.Hereinafter provide usefulness bioadhesive polymer the illustrative goods and also can be at U.S. Patent number 2,810,716 and the patent No. 3,202,577 in find.
Polymer of the present invention also can be prepared described in the European Patent Application No. 88112198.2 that was disclosed as 0 301 532 A2 on February 1st, 1989.According to its description, in the presence of suitable free radical starting material in 45-65 ℃ and pressure more than the mixture critical point, as under 45 ℃ of about 1250 pound per square inches, acrylic acid and cross-linking agent being reacted in as the carbon dioxide of solvent so that meticulous, fluffy polymer to be provided.
Bioadhesive polymer used herein is a graininess or fibrous, is inflatable and insoluble in water.The characteristic that claims bioadhesive polymer polymer of the present invention is for being that inflatable and insoluble this polymer that means can absorb the moisture of 1～100 times of its weight of general pact but makes for fully insoluble that concentration with 0.2% weight provides measurable viscosity in pH6.5 water in water in water.
Bioadhesive polymer polymer of the present invention is expandable in water, that is, when water exists this polymer beads absorb moisture and therefore volume become bigger.Be used for that this expansible moisture is generally provided by Aquo-composition of the present invention or it can be partly be provided by the health of treatment animal, rising or the secretion as percutaneous moisture content, by the mucosa transpiration in the secretion process, as the secretion of saliva or vaginal mucus, or the secretion by tear in the eyes.Yet thereby the body exudates of having noticed the latter does not generally exist or have the demand that causes this compositions with less relatively amount.
The particulate size of bioadhesive polymer has influence to compositions of the present invention.Obviously this bioadhesive polymer granule should consequently just can not used said composition without too many difficulty too greatly.Similarly, when being applied to eye, oral cavity or vagina, cause pain and stimulation sometimes greater than the following granule that size is discussed.As if in addition, on size, promptly on the longest one dimension, bigger granule is compared, improved function is provided for the humidizer compositions with the equirotal granule of discussing below.
In general, Zui Da useful organisms adhesive agent polymer size can be passed and be had 400 purpose sieves screenings (Unite States Standard molecular sieve system); I.e. 38 microns perforate.Preferably, thus this bioadhesive polymer polymer beads is littler to make the longest one dimension be about 20 microns.Most preferably, the longest one dimension of this granule has about 2～5 microns mean size.For example, by grinding, pulverize or otherwise the granule pulverizing larger particles and can obtain required size by direct polymerization.
Compare with having quite large-sized granule, have quite undersized granule per unit weight and have bigger surface area, expand faster and show better adhesion.For convenience, be stranded in 40 order molecular sieves (Unite States Standard molecular sieve series) with passing 30 order molecular sieves screenings, i.e. the bioadhesive polymer of the 30/40 order size bioadhesion measurement carrying out the front and hereinafter discussed among the embodiment 2.
Find that bioadhesion is not the function of bioadhesive polymer molecular weight.Therefore, as long as the adhesive attraction in its described hereinafter adhesion test is at least about 50 dyne/cm 2And preferred about 380 dyne/cm 2, then this bioadhesive polymer can have any molecular weight basically.
As previously mentioned, bioadhesive polymer can prepare by polymerization in water-bearing media.In preferred practice, water-bearing media is the saturated solution of alkali salt such as magnesium sulfate.Alkali salt has at least 2 kinds of functions.At first, thus its density that increases polymerisation medium makes polymeric bioadhesive polymer swim in the water-bearing media surface and can easily therefrom remove.The second, thereby especially having reduced the expansion of bioadhesive polymer in water-bearing media, the use of magnesium sulfate helps polymerization and recovery.
Behind some water flushing polymer like this bioadhesive polymer of preparation generally contain 0.5%～1% the alkaline-earth metal ions of having an appointment.Therefore these polymer are different from that alkaline earth metal hydroxide wherein is used for calcium or magnesium polycarbophil and those polymer of carboxyl.
Commercial available particularly preferred bioadhesive polymer has by Richmond, the material of the polycarbophil by name that the A.H.Robins company of Virginia sells and also this paper discuss by Cleveland, the B.F.Goodrich chemical company of Ohio, CARBOPOL 934 manufacturer sells is also referred to as CARBOPOL 976 CARBOPOL " EX55 ".American Pharmacopeia (U.S.P) was compiled in 1980, the American Pharmacopeia conference, Inc., Rockville, Maryland, illustrated that in 638 pages polycarbophil is and the crosslinked polyacrylic acid of divinyl ethylene glycol, its combustion residue and absorbing power that has less than 4.0% is its about 60 times original weight of absorption in test B.The U.S.P.1985 version is only listed the WL-140 that contains 18-22% calcium and is different from the material described in the version in 1980.
The material of " EX55 " by name of above-mentioned B.F.Goodrich company has about 1.4 proportion and absorption (absorbing and absorption) about 60～100 times water of its weight.This absorption value is similar to natural mucinous absorbability.On the contrary, it is reported CARBOPOL 934 absorb the moisture of hundreds of times of its weight.Useful bioadhesive polymer also is that charge density is similar to mucinous multi-anion copolymer.
Measure the density of the useful bioadhesive polymer of the present invention, it is generally about 1.30～1.70 gram/cubic centimetres (g/cc), or about 1.30～1.70 proportion.As shown in the table, find that crosslinked percent has less influence to the density of the synthetic polymer of the illustrative of gained.In 11 hurdles of this table, also shown U.S. Patent number 4,615,917 content.
The bioadhesive polymer humidizer provides the amount of the humidification of required time to be present in the present composition with the individuality that is enough to need are used the present composition, and such amount this paper is called " effectively amount of humidification ".As everyone knows, the effective dose of reagent is along with used concrete reagent, the symptom of being treated with contain speed that this combination of agents thing gets rid of and change with its used animal from health.Therefore, the effective dose of humidizer can not limit every kind of reagent.
Therefore, effectively amount of humidification for humidizer that q.s is provided in the present composition so that the amount to the required humidification of the body of mammals required time of being treated to be provided.Therefore effective dose also may be defined as amount of humidification.
The humidifying composite that is designed for the inventive method is to provide the bioadhesive polymer of about 0.25～15 gram (g) of per 100 milliliters of compositionss (about 0.25～15% weight).More preferably, the bioadhesive polymer polymer exists with about 2～5 grams (about 2～5% weight) in per 100 milliliters of compositionss.
The moisture of humidification can be provided by compositions or the epithelium that is contacted or both.Therefore, the bioadhesive polymer humidizer can be before use disperses in water-bearing media or pre-the expansion, or dry and anhydrous use or be scattered in and contain enough moisture to use in the particulate carrier of partially hydrated bioadhesive polymer humidizer.
Except water and above-mentioned bioadhesive polymer polymer, the present composition preferably contains the thickening agent of the level and smooth amount of thickening, and the latter is water solublity or aqueous dispersion polymers.
Even thereby thickening agent used herein has enough water solublity or a small amount of viscosity that also can change Aquo-composition substantially of aqueous dispersion ability.Such material can show the bioadhesion effect, but because its solubility or dispersibility in water-bearing media, they tend to lose from compositions quickly and thereby can not provide the humidification effect of the long duration that is provided by aforementioned bioadhesive polymer polymer.
In order to be easy to express, thickening agent generally will refer to water dispersible property in this article.
No matter thickening agent disperses or real dissolving, in deionized water or distilled water forming single phases in 20 ℃ under the compositions naked eyes that reach about 10% this thickening agent that exists, and in case form, when when keeping 24 hours for 20 ℃, still not occurring separating.When thickening agent is when acid, the cation such as sodium, potassium and the ammonium ion that are used for dispersing or dissolving consistency modifiers also can be present in compositions.
The example of thickening agent comprises that anion (containing carboxyl) and non-ionic polymers are as the polymer that contains a plurality of carboxyls with contain a plurality of C 2-C 3The polymer of hydroxyalkyl.Particularly preferred thickening polymer reagent comprises that carboxymethyl cellulose, hydroxypropyl cellulose, hetastarch derivant, hydroxyethyl-cellulose, natural gum are as tragacanth, hydroxy ethyl methacrylate or methacrylate, polyacrylamide and lightly crosslinked acrylic acid polymer, as preferred especially above-mentioned CARBOPOL 934.It is reported CARBOPOL 934 is the polymerizing acrylic acid thing, and it is crosslinked that acrylic acid and per molecule on average contain the polypropylene sucrose (polyalkenyl sucrose) of at least 3 acrylic.Therefore the preferred thickening polymer is regarded as deutero-polysaccharide and polyacrylic acid; Be amide and hydroxyl ethyl ester.Other thickening polymer reagent comprises polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol oxide.
The effect of thickening agent in compositions as herein described is as its title hinted; Promptly increase the denseness of compositions.This potentiation shows 2 aspects: viscosity and quality.
As setting forth, thickening agent used herein is that more a spot of this material water dispersible and relative can increase the viscosity of Aquo-composition greatly or make its retrogradation.Because bioadhesive polymer is only given the viscosity of the quite faint control of Aquo-composition and is set up effect, may be too rare and too soft or too hard for specific purpose such as vagina product so only contain the compositions of bioadhesive polymer humidification polymerization agent.
When mixing with following amount and condition, bioadhesive polymer humidification polymer and thickening polymer are united the moisture humidifying composite that suitable thickening is provided.
The quality ratio of the thickener composition that a beyond thought especially effect of useful bioadhesive polymer humidification polymer and thickening polymer reagent mix is a gained becomes more satiny when using bioadhesive polymer humidification polymer separately.Therefore, the aqueous polymers that only contains bioadhesive polymer humidification polymer may show rigidity and the sensation as the grit almost, so it may be uncomfortable in the vagina product, particularly in the sexual intercourse process.
On the other hand, thus the existence of thickening polymer reagent unexpectedly makes aqueous polymers that more satiny its that become do not show rigidity or grittiness basically.The satiny of quality also provides better lubricity to compositions.
The use of a thickening polymer amount of reagent can provide required thickening and increase soapy feeling.Therefore, using this amount of substance to be described as thickening smoothly measures.Thickening agent can be single polymer or those mixture of polymers as described above.
Thickening polymer reagent exists with the level and smooth amount of thickening, and it preferably provides tremelloid viscosity with the composition that other can be present in the Aquo-composition, and the viscosity when recording 25 ℃ of this products by embodiment 6 is described is about 4,000～40,000cps.As hereinafter going through, composition viscosity is the function of several variablees, and each variable can change with change or keep required viscosity.
Typical compositions can contain the thickening polymer of 0.25～10 percent by weight of having an appointment.What more particularly use is about 0.5～5 percent by weight.
Relatively large thickening agent generally uses with the bioadhesive polymer polymer than a small amount of, and vice versa.For example, contain the CARBOPOL of 0.25 percent by weight polycarbophil as about 8～10 percent by weight of pH value 2.2-2.5 compositions needs of bioadhesive polymer 934 to reach the viscosity that is suitable for machinery placement in vagina.
The moisture of humidification can be provided jointly by compositions or the epithelial cell that is contacted or both, although in general provide moisture content by compositions.Therefore, bioadhesive polymer humidizer and preferred this thickening agent can mix in water-bearing media and pre-the expansion before use, or can mix in the aqueous carrier of partially hydrated bioadhesive polymer humidizer granule and thickening agent and use containing enough moisture.
Useful Aquo-composition can have the room temperature viscosity of dumpable hardly liquid to gel, the latter is preferred, its viscosity is relative quantity, the osmotic pressure of formed compositions and the function of pH value of water, bioadhesive polymer humidification polymer, thickening polymer reagent (when existing).Quite a spot of polymer produces rarer compositions relatively than more substantial polymer in the water of specified rate, and wherein pH value is kept stable under 2 kinds of concentration.
The pK of useful bioadhesive polymer humidification polymer aBe about 3～4.As a result, if the pH value of compositions is about 5～6 or higher, all basically acid protons are neutralized and the compositions table that contains polymer reveals the most heavy-gravity viscosity under this concentration.On the other hand, be as 2 at pH value, be lower than polymer pK aDuring value, for given concentration, said composition is rarer relatively.
The thickening agent such as the particularly preferred CARBOPOL that contain carboxylic acid 934 pK aValue is similar to the pK of bioadhesive polymer polymer aValue.As a result, when keeping constant, be about 5 or use compositions that the most heavy-gravity compositions is provided when higher, provide the rarest compositions and be about 2 o'clock use at pH value at pH value for the thickening agent of given concentration and all other compositions.Non--ionic thickening agent is littler than anionic species viscosity and viscosity-modifying of compositions to them in the pH value scope.
In addition, the permeability of compositions also works in the viscosity of compositions.In general, keep when constant when bioadhesive polymer polymer, thickening polymer reagent (when existing), water and pH value, higher solute concentration reduces the viscosity of compositions.Therefore, by increasing the permeability of compositions, the foregoing viscosity that has greater than 5 pH value can be reduced to dumpable liquid from strong gel.
Deng oozing the permeability that product has about 280～320 mOsM, and this permeability is useful in this article.The permeability of humidifying composite may be up to 450～500 mOsM.
Pharmaceutically acceptable electrolyte and non-electrolyte (being referred to as solute) are used to regulate the permeability and the viscosity of useful composition.The pharmaceutically acceptable electrolyte of illustrative comprises sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium sulfate and potassium, sodium bicarbonate and potassium.The pharmaceutically acceptable non-electrolyte of illustrative comprises that glycerol, sugar are as dextrose plus saccharose, Sorbitol and carbamide.Therefore, those solutes that are used to regulate Morie osmolarity or Osmolality as everyone knows are useful at this paper.
The permeability of given compositions is to press meter and the measured value of acquisition with gas-phase permeation.
Therefore, carboxylic thickening polymer reagent is in the compositions that comprises bioadhesive polymer humidification polymer or be about 5 or demonstrate more gel sample characteristic when higher near aforementioned upper limit of concentration and at pH value having or do not have.Yet this compositions can the form with drop be extruded from the eyes dropper, particularly when existing enough electrolyte or other solute to increase to permeability near about 450 mOsM.On the contrary, unless there is a large amount of bioadhesive polymer polymer, generally show as dumpable hardly liquid otherwise be in or be lower than about 3 compositions near aforementioned concentration limit and pH value.
In concrete example, the compositions that is used for the vagina humidification can show about 4,000～40 at 25 ℃, the viscosity of 000cps, and that the compositions that is used for the oral cavity humidification shows at 25 ℃ is about 1～4, the viscosity of 000cps.More heavy-gravity compositions generally shows non-Newtonian fluid (non-Newtonian flow) feature.Therefore the viscosity of this solution is to measure in particular for the viscometer of said composition design.The viscosity that is used for viscosity measurement of this paper discussion is counted commercial available Haake ROTOVISCO RV-12 type, and can be from Haake, Inc., and 244 Saddle Brook Road, Saddle Brook, New Jersey07662 obtains.When using SV cup and SVII rotor to be used for changeing the shear rate of (rpm) and 25 ℃ with per minute 1-8, measures by this machine viscosity with centipoise (cps) expression.
After remembeing these viscosity limit, the technical staff can easily prepare the humidifying composite with required viscosity.Contact with epithelial tissue in case it is also to be understood that compositions, owing to use the local pH value factor in the zone of compositions, the pH value of humidifying composite can change.
Humidifying composite is administered to epithelium to be enough to the being formed on particulate amount of the successive basically one deck hydration of application surface bioadhesive polymer.In general, this one deck is several particulate thickness.With regard to exsiccant bioadhesive polymer humidizer, this bioadhesive polymer humidizer is with every square centimeter of (cm 2) amount of epithelial cell about 1～50 milligram (mg) of contact uses.Can and preferred surpassing provide humidification required amount to using of epithelium.
The amount of using also is to use the function in site.For example, need quite a spot of total humidifying composite for using of eyes, because when any allogenic material enters eyes, all may cause discomfort.On the contrary, can be to using of skin and vagina epithelium above providing humidification required amount.
For example, about 0.025～1.0mg/cm 2The humidification polymer be used for (about 25～50 microlitres contain the compositions of about 1～3 percent by weight polymer) humidifying composite of eyes, and about 10～50mg/cm 2The humidification polymer be used for humidification skin.
For using of oral cavity, nasal cavity, rectum and vagina epithelium, more convenient with reference to the amount of the bioadhesive polymer humidification polymer of using with regard to the gross weight of using polymer.Therefore, for oral epithelium, use the compositions that contains about 0.25～5 percent by weight bioadhesive polymer humidification polymer.Particularly for vagina epithelium, the amount of compositions is the compositions that contains about 1～5 gram of 0.25～3 percent by weight bioadhesive polymer polymer of having an appointment.The latter's amount surpasses and to be used for the required amount of humidification, but the amount that surpasses lubricated in the sexual intercourse process is provided is useful.So, in a broad sense, fluid composition contains the bioadhesive polymer polymer or the humidizer of 0.25～5 percent by weight of having an appointment.
Except bioadhesive polymer polymer humidizer and thickening agent, useful in the present invention compositions also can contain one or more medicinal upward acceptable additives that is referred to herein as adjuvant of going up or make up, and they help to satisfy the shelf life of humidification product or client's holding capacity.The adjuvant of illustrative comprises antiseptic, astringent, skin toning agent, skin conditioner, dermal sensation reinforcing agent, emollient, lubricating oil, emulsifying agent, humectant, coloring agent and the reagent (odorant agent) of abnormal smells from the patient is provided.
The typical antiseptic that becomes known in the humidizer comprises ethanol, ascorbyl palmitate, benzoic acid, the fourth hydroxyanisol, butylated hydroxytoluene, methaform, ethylenediamine, ethyl p-Hydroxybenzoate (ethylparaben), ethyl vanillin, glycerol, methyl p-Hydroxybenzoate (methylparaben), single thioglycerol (monothioglycerol), phenol, phenethyl alcohol (phenylethylalcohol), phenylmercuric nitrate, propyl para-hydroxybenzoate (propylparaben), Sassafras oil, sodium benzoate, formaldehyde oxygen sodium sulfide (sodium formaldehyda sulfoxylate), sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid and propyl gallic acid.Obviously, aforementioned to a certain extent arbitrary antiseptic has stimulation to sensitive organization, so should select less zest antiseptic.
The typical astringent that becomes known for humidizer has (1) aluminum, zinc, manganese, ferrum and bismuth salt, and (2) contain some other salt (as permanganate) and (3) tannic acid or relevant polyphenolic substance of these metals.
The typical emollient that becomes known for humidizer penetrates into surface layer by emollient and makes skin become more pliable and tougher for being used for remollescent bland fatty or oily matter.The typical emollient of known use comprises mixture, Oleum sesami, oleum theobromatis, myristyl alcohol and the shark liver oil of mixture, dodecyl sodium sulfate, propylene glycol and the stearyl alcohol of Oleum Ricini, Sulfated Oleum Ricini, cupu oil, cold cream, Semen Maydis oil, Oleum Gossypii semen, rose water ointment (being also referred to as cold cream), white beeswax and white vaseline.
The typical lubricants or the lubricating oil that become known for humidizer have vaseline, white beeswax or Cera Flava, cupu oil, oleic acid, olive oil, simmondsia oil, paraffin, glycerite starch, lanoline, paraffin, hydrophilic vaseline, mineral oil, spermol, glyceryl monostearate, lanoline, stearic acid, Polyethylene Glycol, polyoxy 40 stearates, multi-sorbitol ester, cholesterol and macromolecule lipid.
Emollient and lubricant provide the skin-protection product that has suitable level and smooth sense of touch and be rubbed into characteristic to strengthen easy-to-use and the encourage consumer more arbitrarily and continually uses this product.The chemical compound of some allows to mix with glycerol and be used to not have such as the such material of vaseline the personal care product of soapy feeling.Vaseline-glycerol mixture is effective especially to alleviating exsiccant skin.
The typical emulsifiers that becomes known for humidizer has sodium alginate, carbopol preparation, sodium carboxymethyl cellulose, carrageenan, gelatin, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, octoxynol9, oleyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone, dodecyl sodium sulfate, sorbitan ester, Solsperse 2000, tragacanth, reaches xanthan gum.Emulsifying agent is used for preparing the water oil emulsion and can be divided into 3 types: unimolecule, polymolecular and solid particle.Known unimolecule emulsifying agent comprises potassium laurate, polyoxyethylene sorbitan monoleate.The polymolecular emulsifying agent comprises acacin and gelatin.The solid particle emulsifying agent comprises Bentonite, graphite and magnesium hydroxide.Emulsifying agent also can chemically be divided into anionic, cationic and nonionic.
The typical wetting agent that becomes known for humidizer has glycerol, propylene glycol, 2-pyrrolidone-5-carboxylic acid, sodium lactate, carbamide, reaches some natural lipid mixtures.Other known wetting agent comprises some albumen, gelatin, hyaluronic acid, vitamin and some natural components.Some used albumen is collagen protein, hyaluronic acid, elastin laminin, placental protein and also uses albumen from mammalian epithelial tissue.In general, wetting agent works by the amount of passing horny layer and increase and horny layer lipid or the closely-related maintenance moisture of albumen.
These goods by under the temperature and pressure that increases to be enough to the killing level of all bacterial pollutants and the time autoclaving becomes aseptic or they are prepared under aseptic condition.
These goods can become apyrogeneity from the pyrogen-free water that commercial laboratory obtains by using.
Phrase such as " medicinal acceptable ", " acceptable in the cosmetic " or " can tolerate on the physiology " used herein is meant that described material can be used for people or other mammiferous treatment are not caused sick effect, as to the toxicity of mucosa or skin histology, blister or bleach, and these materials itself are not the bioadhesive polymer humidizers, as those words used herein.The adjuvant of illustrative can be at the Lei Mingdun pharmaceutical science, and the 16th edition, volumes such as Osol, Mack publishing company, Easton finds in 84 chapters of 67 chapters among the PA (1980) and the 17th edition.
Noticed that adjuvant above-mentioned can exist with the amount greater than the bioadhesive polymer polymer.Even situation is like this, but adjuvant does not provide the humidification of compositions, but emulsifying or effect such as lubricated are provided, and generally helps using of compositions.If chemical compound, as situation comes to this when being known as the glycerol of wetting agent or sorbitol and existing, because these materials are water miscible abiotic adhesive agents, generally loses with perspire etc.Lubricating oil and emulsifying agent provide the lubrication of sexual intercourse compositions.
Can be used as dry powder, aqueous suspensions or non-aqueous suspensions and use the useful humidifying composite of this paper with contact skin.Using of this compositions can be the sprinkling of powder or suspension, or drips, to the form with emulsifiable paste or gel sample toughness.
In one embodiment, exsiccant bioadhesive polymer humidification polymer expands in water-bearing media when required pH value, is used to contact required tissue such as eyes then.The word " drying " relevant with bioadhesive polymer humidification polymer used herein is meant when contacting with the finger in the rubber gloves and do not adhere to, and do not expand basically.
Bioadhesive polymer also can be used as the medication that suppository is used for rectum or vagina, and wherein the bioadhesive polymer polymer dispersed is in wherein.The particulate rare aqueous dispersion of bioadhesive polymer humidification also is useful as vagina or rectal irrigation liquid.Preferred tremelloid toughness is used for the vagina humidizer, and compositions is carried out medication with the plunger shape medication device that is used to use the vagina product as everyone knows.
In another illustrative embodiment, the bioadhesive polymer humidizer with acceptable aqueous carrier uniform mixing to be used for eyes as the medicinal of diluent.This bioadhesive polymer is preferably ground or otherwise is made on average about 2～5 microns size of the longest one dimension to be used for eyes.Zhi Bei compositions can be used as drop then and splashes in the anterior angle membrane vesicle (precorneal pocket) of eyes contacting with conjunctiva like this, and therefore contacting of humidifying composite and mucosa be provided.
Implement best mode of the present invention
Embodiment 1: the preparation of bioadhesive polymer polymer
Bioadhesive polymer polymer used herein prepares by the following general synthetic method that is about to discuss.By the explanation in the table 1 hereinafter of the concrete bioadhesive polymer polymer of general synthetic method preparation.
Contain 100 ml distilled waters and 800 gram magnesium sulfate (MgSO 4-7H 2O) solution stirring is heated to backflow.1 gram starting material is dissolved in mixture that forms in the 100 gram monomer carboxyl functional group recurring units and the lasting recirculation water solution that stirs of amount adding that is shown in the cross-linking agent in the table 1.The polymeric compositions of preparation is like this stirred and is heated to the temperature during starting polymerization and the polymerization after-hardening of being used for shown in the table 1.
When firm time finished, polymeric compositions was heated to about 95 ℃ distilled water diluting with 150 milliliters, filtered with having 40 purpose stainless steel sifts (Unite States Standard sieve series) then.Being stranded in filtering biological adhesive agent on the sieve is heated to about 80 ℃ water washing with 1 liter and uses 1 liter Warm Wash 5 times more respectively.Then the bioadhesive polymer of the washing that will prepare like this in the blowing-type baker 90 ℃ of dryings 48 hours.
The bioadhesive polymer that will prepare so directly uses or grinds and sieves so that required particulate size to be provided then.
Table 1
Bioadhesive polymer carboxyl functional group polymerizing condition recurring unit 1Cross-linking agent 2Starting material 3Polymerization time 4T 5Time 6Output 7(A) (a) (b) (a) (b) 1.0 (1) 30 95 48 87 (C) of 1.0 (1) 30 95 48 53 (B) of 1.0 (1) 25 95 18 67 (B) of 0.2 (1) 15 95 2 83 (A) 8(a) 1.0 (1)--65 24 11 (D) 8(a) (c) 0.2 (1) 10 95 4 98 (B) (c) 0.2 (1) 10 95 20 93 of 0.2 (2) 20 95 72 10 (A)
Each 100 gram of the following carboxyl functional group of 1 use recurring unit: (A)=acrylic acid; (B)=methacrylic acid; (C)=methylene succinic acid; And (D)=maleic anhydride.
The gram number of the concrete cross-linking agent that the numeral in 2 tables is used.Concrete cross-linking agent is: (a)=3,4 dihydroxy-1,5-hexadiene; (b)=divinylbenzene; And (c)=2,5 dimethyl-1, the 5-hexadiene.
3 have used the initial substance below 1 gram: (1)=benzoyl peroxide; (2)=the two isobutyl moon of azo green grass or young crops.
The number of minutes of 4 starting polymerization times.
The temperature of 5 starting polymerization and polymerization after-hardening (℃)
The hourage of 6 polymerization after-hardening times.
The productive rate of the 7 dry bioadhesive polymers that calculate according to the weight of the bioadhesive polymer of initial substance and recovery.
Use nitrogen jet in 8 polymerization processes and prepared airfree distilled water in 10 minutes by boiling distilled water.
Though the optimization of polymerizing condition does not reflect in the data in table 1, can prepare the useful bioadhesive polymer of this paper of useful amount from these data as can be seen at an easy rate.First kind of bioadhesive polymer should noting listing in the table 1 has substantially the same in commercial available by Richmond, the material of the polycarbophil by name that the A.H.Robins company of Virginia sells, with by Cleveland, the bioadhesion effect of the material that is called EX55 that the B.F.Goodrich chemical company of Ohio sells and other physicochemical properties.
Embodiment 2: adhering mensuration
As previously noted, bioadhesive polymer humidification polymer of the present invention is water-insoluble and water-swollen graininess, fibrous crosslinked carboxyl functional group polymer, and it contains the carboxyl functional group and the cross-linking agent of specified quantitative.In addition, as for its chemistry definition, the useful organisms adhesive agent of definition is when at U.S. Patent number 4,615, when the specified conditions of embodiment 2 regulations are measured down in 697, also must demonstrate at least about 50 dyne/cm between the rabbit gastric tissue of 2 new excisions 2Viscosity.
The result of the illustrative that 4 kinds of useful bioadhesive polymers obtain with top measuring technique hereinafter has been described in the table 2.Except the cross-linking agent that uses 0.3 percent by weight, described in embodiment 1, prepare bioadhesive polymer.After the preparation, this bioadhesive polymer is screened and the dried granule that will have 30/40 an order size (Unite States Standard sieve series) is used for these mensuration.
Table 2
Bioadhesion is measured polymer 1The weight of tissue to be separated 2The active force of chorista 3The number of measuring
1 855±55 1061±68 13
2 864±56 1072±68 12
3 876±57 1086±71 13
4 306±45 380±56 8
1 polymer 1=and 3,4 dihydroxy-1, the polyacrylic acid that the 5-hexadiene is crosslinked; Polymer 2=and 2,5 dimethyl-1, the polyacrylic acid that the 5-hexadiene is crosslinked; The polyacrylic acid of polymer 3=and divinylbenzene crosslink; And the polymethylacrylic acid of polymer 4=and divinylbenzene crosslink.
2 weight are with standard error (S.E.M) expression of milligram ± meansigma methods
3 active forces are with dyne/cm 2± S.E.M represents.
With above-mentioned determination techniques, commercial can be from Milwaukee, the p-HEMA that the Aldrich chemical company of Wisconsin obtains needs the active force of 29 dyne/cm to come chorista, and can be from Philadelphia, the AMBERLITE that the Rohm of Pennsylvania and Haas company obtain 200 cation exchange resin choristas need active force hardly.
Embodiment 3: as the adhesive attraction of pH value function
The active force of measuring that is used for separating bio adhesive agent polymer is shown in Fig. 2, and bioadhesive polymer polymer wherein is 3 of polyacrylic acid and 0.3 percent by weight, 4-dihydroxy-1, the polymeric product of 5-hexadiene and have the density of 1.56 g/cc.As shown in the figure, observed maximum adhesive attraction at about 5～6 o'clock at pH value.This maximum is pH value 0.46,1.42 or was used to separate more than 2 times of required adhesion at 2.0 o'clock.Visiblely in addition be that the adhesive attraction that is provided by this bioadhesive polymer polymer is to reduce greatly in 7 o'clock at pH value.This minimizing is significant on the statistics in student t-check, and p is less than 0.01.Bioadhesion power is measured described in front embodiment 2.
Embodiment 4: the method for the dry vagina of moistening
By mixing preparation as Emulsion, contain that size can be passed 400 order molecular sieves (Unite States Standard sieve series) and its longest average one dimensional numerical is no more than about 20 microns polycarbophil (20g, B.F.Goodrich Ex55), CARBOPOL 934 (10 g, B.F.Goodrich), hydrogenant Petiolus Trachycarpi oil glyceride dispersant [10 g, MYVEROL 18-04K (Eastman)], black mineral oil (U.S.P. black mineral oil; 50 ml, Purepac), (100 ml, Purepac), methyl p-Hydroxybenzoate (1.0 g) also adds the humidifying composite of distillatory deionized water to 1000 g to U.S.P. glycerol.With the sodium citrate solution among the HCl pH value is adjusted to 2.4.
About 4g above-mentioned composition places plunger piston type medication device.Medication device and content thereof are placed the vagina that shows vagina drying and colpitic postmenopausal women, and the extruding plunger enters experimenter's vaginal canal with the contact vaginal mucosa to force compositions.The compositions of using has like this increased the moisture of mucosa and also provides lubrication for sexual intercourse.
Embodiment 5: the viscosity comparative study
Preparation basically with 3 kinds of identical moisture vagina humidifying composites of compositions among the embodiment 4, but wherein change and as the CARBOPOL of thickening agent as the amount of the polycarbophil of bioadhesive polymer humidification polymer It is constant that 934 amount keeps, and uses moisture completion compositions more or less.
These 3 kinds of compositionss all contain the CARBOPOL of 1 percent by weight 934.Compositions 1 contains the polycarbophil of 1 percent by weight.Compositions 2 with the same among the embodiment 4, contain the polycarbophil of 2 percent by weight, and compositions 3 contains the polycarbophil of 3 percent by weight.Although too rare its had the viscosity of emulsifiable paste when compositions 1 was considered to use.Compositions 3 is too thick for disperseing.Compositions 2 is for having suitable viscosity and demonstrate good sensation with plunger piston type medication device disperses when wiping skin.
Embodiment 6: the mensuration of viscosity
Humidifying composite of the present invention is a viscosity, preferably has the gel sample toughness slightly thick or more more tacky than mayonnaise.Such compositions table reveal can be described as thixotropic non--the Newtonian fluid feature; Be that characteristic of fluid is 1) the flow point, 2) the pseudoelastic properties behavior, 3) in the limited time, can see the decline and 4 of continue shearing medium viscosity) trend of when static, rebuilding viscosity and/or flow point.
Because the non--Newtonian fluid feature of expection humidifying composite, viscosimetric analysis is used at the specially designed viscosity agent of this fluid and is carried out.Therefore, with specific viscosity agent, the viscosity number when temperature and shear rate shown in being reported in.
The viscosity that is used for viscosity measurement of this paper discussion is counted commercial available HaakeROTOVISCO RV-12 type, can be from Haake, and Inc., 244 Saddle Brook Road, SaddleBrook, New Jersey 07662 obtains.This machine uses SV cup and SVII rotor to be used for changeing under the shear rate of (rpm) and 25 ℃ with per minute 1-8 and measures viscosity with centipoise (cps).
Humidifying composite by 2 kinds of illustrative of preparation described in the embodiment 4 is prepared respectively by different people.1,2, the shear rate of 4 and 8 rpm is measured the viscosity of 2 kinds of compositionss down, and compares then respectively.
This comparative result is shown among Fig. 3, wherein with viscosity n (cps * 10 4) to shearing ratio n (rpm) mapping.The data point that shows 2 kinds of different components with hollow and solid garden.
Embodiment 7: the comparison of vagina humidification
Under qualified internist's guidance, carry out the double-blind study of vagina humidification with a kind of humidifying composite and method of the present invention (embodiment 4) and a kind of commercial available vaginal lubrication product, its manufacturer of lubricated product wherein is described as not having greasy, water miscible lyogel, it is limpid, easily diffusion and nonirritant.89 intimate menopause or postmenopausal women in this research, have been registered altogether.Totally 8 experimenters have withdrawed from research because of a variety of causes.
Before the research beginning, every registrant is carried out medical history and physical examination completely.Carry out examination per vagina and adopt the PAP smear being used for the colpocytology inspection.Carry out the vagina drying index determining, comprise the measurement of pH value.
2.5 in the continuous vagina that inserted the registrant in 5 days at night of any in 2 kinds of compositionss of gram fixed dosage.Do not use compositions at 6-8 days.
Vagina drying index, vagina pH value and PAP smear were measured at 5-8 days.The registrant used other compositions and write down above-mentioned data at 13-16 days once more at 9-13 days.Also require the experimenter to do diary during the research, and inform and during studying, keep their normal sexual intercourse custom, and advise during studying, not using intravaginal drug, comprise washing liquid.
Most of experimenters (57.5%) used vaginal lubricant in the past, and the reason that great majority (71.4%) report is used is a vagina pain.The regular vagina drying of 37.6% subjects reported, discontinuity be 31.8%, begin for discontinuity now for regular be 30.6%.The result measures with statistical method.
This result of study may be summarized as follows:
(1). when using compositions of the present invention, vagina pH significantly descends (0.01 level) statistically, and pH value does not descend when using commercial available lyogel.After said composition was used about 48 hours for the last time, the vagina pH value maintained about pH5 or lower.
(2). the humidification effect of gel combination of the present invention is than using commercial product to be tending towards continuing the longer time (p＜0.001).The experimenter of more uses gel of the present invention reports the humidification duration of effect and surpasses 12 hours, and the commercial product lyogel is reported to more continually and continues less than 6 hours.
(3) when asking about them and like any compositions, 61.5% agrees with compositions of the present invention, and 25.6% agrees with the coml lyogel.
(4) great majority are accepted women's existence of gel combination of the present invention or are partly had the pudendum humidification.Compare with using compositions of the present invention, the subjects reported of the commercial lubricating fluid gel of more uses has leakage.Use experimenter's neither one report pudendum moisture of gel of the present invention to increase too much, and use the experimenter of commercial lubricating fluid gel to have 40% report pudendum moisture to increase too much.
When (5) using commercial lubricating fluid gel, there are 10 its state of an illness of women report to increase the weight of, by contrast, use gel of the present invention to have only 1 its state of an illness of women report to increase the weight of.There are 5 women report to use 2 kinds of its state of an illness of compositions all to increase the weight of simultaneously.Women with the commercial lubricating fluid gel of water solublity does not report that residue is arranged, and by contrast, uses the women of gel of the present invention to have 7.8% report that residue is arranged.
(6) use gel of the present invention than using commercial gel mucosa better quality (rank higher).Although, do not have the significant difference on the statistics between the use of these 2 kinds of compositionss using the significant difference that exists between this gel combination and the pretreated control value on the statistics.
(7) with gel combination of the present invention and control value and to use the value of commercial available lubricating fluid gel to compare moisture level obviously higher statistically.
The vagina drying index evaluation is 5 parameters, supposes every kind of digital score that 1-5 is arranged, and is the best with 5.Like this, score is low more, lacks the vaginal lubrication effect more.
5 parameters and score (parenthetic) thereof are as follows:
1. overall vagina elasticity
(1) do not have, (2) are faint, and (3) are general, and (4) are good, and (5) are outstanding;
2. vaginal secretions type and toughness
(1) do not have, (2) are a small amount of rare and yellow, the thin layer that (3) are rare and white, and one deck of the intermediate gauge that (4) are rare and white, (5) are normal [white
Color is cotton-shaped];
3.pH value
(1) 6.1 or higher, (2) 5.6-6.0, (3) 5.1-5.5, (4) 4.7-5.0, (5) 4.6 or lower;
4. vaginal mucosa
(1) notice ecchymosis before the contact, (2) highly contact 10 samples and bleed, and (3) friction is bled, (4) non-easily broken approaching
Mucosa, (5) non-easily broken normal mucosa; And
5. vagina moisture
(1) do not have, the mucosa inflammation, (2) do not have, 15 sample mucosas do not have inflammation, (3) seldom, (4) are medium, (5) are normal.
Embodiment 8: the method that increases dry skin moisture
Contain size and can pass 400 order molecular sieves (Unite States Standard sieve series) and average the longest one dimension by mixing preparation less than about 20 microns exsiccant polycarbophil (5 g, B.F.GoodrichEx55), small silicate granules (3.75 g Syloid, 244 FP, Davison Chemical Division, W.R.Grace ﹠amp; Co., Baltimore, Maryland), light mineral oil (50 ml), the compositions of 95% ethanol (250 ml) and water (capacity reaches the distillation deionized water of 1000 ml).
Zhi Bei compositions is with every 20-30 cm like this 2Need the amount of the about 0.5-1g of skin of humidification to coat the surface of dry skin, and allow its adhesion.The moisture content that polymer composition adheres to contact area and keeps contacting with exsiccant skin surface.
Embodiment 9: the method that increases dry skin moisture
Has about 2～5 microns dry polycarbophil (5.00g of mean particle size by mixing; B.F.Goodrich Ex55) and CARBOPOL 934P (2.50 g), Syloid 244 FP (3.75 g) that contain light mineral oil (50.00 ml), 95% ethanol (250.00 ml), carbamide (100.00 g), methyl p-Hydroxybenzoate (1 g), propyl para-hydroxybenzoate (0.5 g) also is diluted to 1000 ml and prepares compositions with the distillation deionized water.The compositions of gained has greasy texture.
Said composition is used for the treatment of dry skin described in top embodiment 4.Compositions mineral oil in fluid and CARBOPOL 934 existence has improved its quality and has made compositions become more smooth when being applied to skin.
Embodiment 10: the method that increases dry vagina moisture
Compositions, the methyl p-Hydroxybenzoate (0.2 g) of dry polycarbophil (3 g) preparation that will be from embodiment 8, propyl para-hydroxybenzoate (0.03 g) and water (100 ml) mix and stir, and with the sodium citrate solution among the HCl pH value are adjusted to 2.4.Zhi Bei compositions has tremelloid toughness like this.
About 4 g above-mentioned compositions place plunger piston type medication device.Medication device and content thereof are placed the vagina that shows vagina drying and colpitic postmenopausal women, thereby and the extruding plunger enter experimenter's vaginal canal contact vagina epithelium to force compositions.The compositions of using like this increases the moisture of mucosa and also provides lubrication for sexual intercourse.
Embodiment 11: the method that increases exsiccant oral cavity moisture
Dry polycarbophil (2.0 g), sorbitol [NEOSORB that will be from embodiment 8 P100T (10g, Roquette company)], aspartame (0.06 g, NUTRASWEET ), Fructus Citri Limoniae-vanilla flavor (1.0 g), methyl p-Hydroxybenzoate (0.20 mg), propyl para-hydroxybenzoate (0.03 g) and water (100 ml) mix and also stir the preparation compositions, and with the sodium citrate solution among the HCl pH value are adjusted to 2.3.
Said composition is applied in the mouth tissue of or dehydration wherein dry with humidification.Similar compositions can be used by multiple administration form, as moisture spray, gel, masticable tablet, exsiccant powder, wafer, pastille, lozenge and Emulsion.Other administration form be prepared by well-known technology and only need to contain above list bioadhesive polymer humidification polymer in the composition.
Regardless of the form that compositions is used, this bioadhesive polymer polymer contact oral cavity membrane tissue also keeps the interior moisture of oral mucosa.
Embodiment 12: the method that increases exsiccant eyes moisture
Polycarbophil (B.F.Goodrich Ex55) is dry, crushing and screening can be passed 400 order molecular sieves (Unite States Standard sieve series) and its longest average about 2～5 microns granule of one dimension to provide.By mixing the compositions of preparation these polycarbophil granules (3.0 g) and water (100 ml), and pH is transferred to about 5.5.Further stir and add electrolyte so that more heavy-gravity liquid to be provided.The amount of this liquid with about 0.025-0.05 ml is administered on the epithelium with the eyes dropper.Remain to treatment target with contacting of forming of eye mucosa since itching of eyes point out need other to treat till.
Above be intended to be illustrative of the invention rather than limiting.Under the situation that does not depart from essence of the present invention and new ideas scope, can realize numerous variations or modification.

Claims (41)

1. the epithelial method of humidification mammal comprises:
The mammal epithelial cell of need humidification is contacted with the Aquo-composition of effective amount of humidification, said composition contains the bioadhesive polymer humidification polymer at least about every square centimeter 380 dyne adhesion of having of water and amount of humidification, and described bioadhesive polymer humidification polymer comprises hydroexpansivity but water-fast crosslinked carboxyl functional group polymer; With
Keep the epithelial cell of described contact time enough with the described contact of humidification.
2. according to the process of claim 1 wherein that described bioadhesive polymer humidification polymer contains a plurality of recurring units, wherein this recurring unit contains 80% carboxyl functional group at least.
3. according to the method for claim 2, wherein said bioadhesive polymer polymer contains 0.01～6% the cross-linking agent of having an appointment.
4. according to the method for claim 3, wherein said cross-linking agent is for being substantially free of the polyalkenyl polyethers.
5. according to the method for claim 3, wherein said Aquo-composition further contains the thickening agent of the level and smooth amount of thickening.
6. the epithelial method of humidification mammal comprises:
The mammal epithelial cell of need humidification is contacted with the Aquo-composition of effective amount of humidification, said composition contains water, having of amount of humidification at least about the bioadhesive polymer humidification polymer of every square centimeter 380 dyne adhesion and the thickening agent of the level and smooth amount of thickening, described bioadhesive polymer humidification polymer comprises hydroexpansivity but is water-fast, granular crosslinked carboxyl functional group polymer, this polymer contains: (a) a plurality of recurring units, wherein contain at least one carboxyl functional group and (b) about respectively 0.01%～6% cross-linking agent and cross-linking agent at least about the recurring unit that contains 80%, described thickening agent is the nonionic or the anionic polymer of water dispersible; With
Keep the vaginal epithelial cell of described contact time enough with the described contact of humidification.
7. according to the method for claim 6, its size can be passed 400 mesh sieves in the Unite States Standard sieve series when wherein said bioadhesive polymer polymer beads was dry.
8. according to the method for claim 7, wherein said thickening agent is the anionic polymer with a plurality of carboxyls.
9. according to the method for claim 7, wherein said thickening agent is present in the described compositions with about 0.25～10 percent by weight.
10. according to the method for claim 7, wherein said bioadhesive polymer polymer beads is scattered in the diluent that can tolerate on the physiology before described contact.
11. according to the method for claim 7, wherein the epithelium that is contacted is selected from skin, vaginal mucosa, oral mucosa, nasal mucosa, anal mucosa and conjunctiva mucosa.
12. epithelial tissue humidifying composite, contain water, having of amount of humidification at least about the bioadhesive polymer humidification polymer of every square centimeter 380 dyne adhesion and the thickening agent of the level and smooth amount of thickening, described bioadhesive polymer humidification polymer comprises hydroexpansivity but water-fast, crosslinked carboxyl functional group polymer, and described thickening agent is water dispersible nonionic or anionic polymer.
13. according to the compositions of claim 12, wherein said bioadhesive polymer humidification polymer contains a plurality of recurring units, wherein contains at least one carboxyl functional group at least about 80% recurring unit.
14. according to the compositions of claim 13, wherein said bioadhesive polymer polymer contains 0.01%～6% the cross-linking agent of having an appointment.
15. according to the compositions of claim 14, wherein said cross-linking agent is for being substantially free of the polyalkenyl polyethers.
16. vagina humidification polymer, it contains water, having of amount of humidification at least about the bioadhesive polymer humidification polymer of every square centimeter 380 dyne adhesion and the thickening agent of the level and smooth amount of thickening, described bioadhesive polymer humidification polymer is gone up substantially by hydroexpansivity but is water-fast, the crosslinked carboxyl functional group polymer of graininess is formed, this polymer contains (1) a plurality of recurring units, wherein contain at least one carboxyl functional group and (b) about 0.01%～6% cross-linking agent at least about 80% recurring unit, described percent is respectively based on the weight of unpolymerized recurring unit and cross-linking agent, and described thickening agent is the nonionic or the anionic polymer of water dispersible.
17. according to the compositions of claim 16, its size can be passed 400 mesh sieves in the Unite States Standard sieve series when wherein said bioadhesive polymer polymer beads was dry.
18. according to the compositions of claim 16, wherein said thickening agent is present in the described compositions with about 0.25～10 percent by weight.
19. humidifying composite, it contains having at least about the bioadhesive polymer humidification polymer of every square centimeter 380 dyne adhesion and becoming known for adjuvant in the humidifying composite of water and amount of humidification, and described bioadhesive polymer humidification polymer comprises hydroexpansivity but water-fast, the crosslinked carboxyl functional group polymer of graininess.
20. according to the compositions of claim 19, wherein said bioadhesive polymer humidification polymer contains a plurality of recurring units, wherein contains at least one carboxyl functional group at least about 80% recurring unit.
21. according to the compositions of claim 20, wherein said bioadhesive polymer polymer contains 0.01%～6% the cross-linking agent of having an appointment.
22. according to the compositions of claim 19, wherein said cross-linking agent is substantially free of the polyalkenyl polyethers.
23., be essentially aseptic preparation according to the compositions of claim 21.
24. according to the compositions of claim 21, it is pyrogen-free basically.
25. according to the compositions of claim 21, it contains one or more antiseptic.
26. according to the compositions of claim 21, it contains lubricant.
27. according to the compositions of claim 21, it contains one or more antiseptic, a kind of lubricant and thickening agent.
28. produce the method for humidifying composite, what comprise mixing water and amount of humidification has at least about the bioadhesive polymer humidification polymer of every square centimeter 380 dyne adhesion and becomes known for adjuvant in the humidifying composite, and described bioadhesive polymer polymer comprises hydroexpansivity but water-fast, the crosslinked carboxyl functional group polymer of graininess.
29. according to the method for claim 28, wherein said bioadhesive polymer humidification polymer contains a plurality of recurring units, wherein contains at least one carboxyl functional group at least about 80% recurring unit.
30. according to the method for claim 29, wherein said bioadhesive polymer polymer contains 0.01%～6% cross-linking agent of having an appointment.
31. according to the method for claim 29, the essentially no polyalkenyl polyethers of wherein said cross-linking agent.
32., then mixture is sterilized then according to the method for claim 28.
33. according to the method for claim 28, then test does not contain pyrogen then.
34. according to the method for claim 28, comprising adding one or more antiseptic.
35., plant lubricant comprising adding one or more according to the method for claim 28.
36. according to the method for claim 28, comprising adding thickening agent and lubricant.
37. according to the method for claim 36, it does not contain pungent.
38. prepare the method for vagina humidifying composite, what comprise the humidification by mixing of gas amount has at least about the bioadhesive polymer humidification polymer of every square centimeter 380 dyne adhesion and the thickening agent of the level and smooth amount of thickening, described bioadhesive polymer polymer comprises hydroexpansivity but water-fast, crosslinked carboxyl functional group polymer, this polymer contains (1) a plurality of recurring units, wherein contain at least one carboxyl functional group and (b) about respectively 0.01%～6% cross-linking agent at least about 80% recurring unit, described thickening agent is the nonionic or the anionic polymer of water dispersible.
39. according to the compositions of claim 38, its size can be passed 400 mesh sieves in the Unite States Standard sieve series when wherein said bioadhesive polymer polymer beads was dry.
40. according to the compositions of claim 38, about 2～5 microns of the longest one dimension average out to of wherein said bioadhesive polymer polymer beads.
41. according to the compositions of claim 38, wherein said thickening agent is present in the described compositions with about 0.25～10 percent by weight.
CN98117463A 1998-09-02 1998-09-02 Tissue humidifying composite and method Pending CN1246369A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102824737A (en) * 2012-09-19 2012-12-19 余子隽 Badminton humidizer and humidifying spraying agent
CN107307936A (en) * 2011-12-01 2017-11-03 Lrc产品有限公司 Band coating condom

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107307936A (en) * 2011-12-01 2017-11-03 Lrc产品有限公司 Band coating condom
CN102824737A (en) * 2012-09-19 2012-12-19 余子隽 Badminton humidizer and humidifying spraying agent

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