CA2097321A1

CA2097321A1 - Contamination-resistant dispensing and metering device

Info

Publication number: CA2097321A1
Application number: CA 2097321
Authority: CA
Inventors: Vlado I. Matkovich; Thomas E. Schlaudecker; Martin W. Henley; Thomas J. Bormann
Original assignee: Individual
Current assignee: Merck and Co Inc; Pall Corp
Priority date: 1990-11-30
Filing date: 1990-11-30
Publication date: 1992-05-31

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to the field of liquid dispensing and metering devices that dispense a solution in drop form and protects the solution from contamination. In applications where contamination and proper dosage is a concern, the prior art discloses dispensers related both to the use of anti-bacterial agents added to the solution to prevent contamination and the use of a single dose device. Both present problems, as the addition of the agent causes allergic reactions in some users, while the single dose device is inconvenient to the frequent user. Prior art dispensers also do not permit control of metering for proper dosage. This invention solves these problems by providing a filter in the dropper portion of the device to prevent contamination of the solution. The device includes a dropper having an outlet and filter. The filter is a composite consisting of a liquophilic component and a liquophobic component.

Description

WO9~/09523 P~T/US90~07029 3 w ~

~1--CONTAMINA~ION-R~SISTANT
DISPENSING ~ND ME~ERING DEVICE

This application is a conti~uation-in-part application of United States Patent Application Serial No. 07~360,041 fil~d June 1, 1989.

Technical Field This invention relates to a liquid dispensing and metering device that is especially useful in, for example, the dispensing of opti~al drugs that typically need to be dispensed in drop form. The present invention provides such a device that also protects the solution *rom contamination while retained in the device.

Background of ~he Invention This invention has wide application in situa-tions where a liquid is required to be dispensed in ~etered amounts at regular intervals from a con-tainer and in which it is critical th~t contamina-~ion from outside~ whether particulate or ~acterial in nature, ~e excluded. By 'imetering" is meant precise control or regulation o~ flow rate. Such a situation is most frequently encountered in the context of the dispensing of medicines such as oph~

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thalmic medicines but ~he utility of the inv~ntion extends to the dispensation and to the protection of any liquid against particulate contamina~ion. For ease of understanding, however, the invention will be described primarily in the context of the appli-cation that, as is presently anticipated, will be the most commercially attractive.
~ any drugs, particularly those used in treat-ment of various eye disorders, are administered in drop form. The drops are intended t~ free-fall onto the eye surface, where they distribute across the exposed eye. Dosage of these ophthalmic drugs is often crucial: lower than prescribed levels can result in failure of the treatment and consequent progression of the dis~ase, higher levels can result in untoward side effects that can also interfere with successful reæolution.
Complicating the administration of these drugs is the fact that they are often re~uired several times a day and thus, to be pract:ical, must be ap-plied by the patients themselves and not by medical per onnel who are formally trained in drug delivery.
Patient administration of such drugs has resulted in two serious problems which must be solved for these medications to be successfully used: container con-tamination and flow rate.

Container Contamination The possibility that bacterial contamination may enter the drug container and proliferate there is an ever-present problem that can destroy the utility of *he medicine. This can be the result of dropper contact with a non-sterile surface, such as a body part, or by some other mechanism.
The problem can be most readily understcod in , WO97/09S23 PCT/US90/07~2~
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the context of the administration of drops of an ophthalmic medicine. Ideally, the pendant drop formed at the tip of the conventional dropper container when the ~ontainer is squeezed should be allowed to free-fall to thP surface of the eye. In addition, the distance between the dropper tip and th~ surface of the eye sho~ld be kept reasonably close~ This is important so that the momentum ac-quired by the free falling drop will not be so great as to encourage the drop to splatter on impact with the eye surface and thus be substantially lost to the outer surface of the lids and face. Wher~
administration is by a trained pro~essional, i~ is relatively easy to ensure that the free-falling ~rop is discharged close to the eye surface. It is sub-stantially more difficult to do this when the drug is self-administered. Gauging such short distances is physiologically difficult due to the inability to focus, and in addition the anticipation of the impacting drop often causes a blink and subsequent loss of portions of the drop. A:s a result, the user may inadvertently permit the dropper tip to contact the eye surface.
In any event, small ~mounts of eye liquids can thus be inadvertently permitted to commingle with the liquid of the drop to be delivered. Thus, when the pressure bn th~ delivery container forcing the drop out is relieved, a small amount of the mixed liquids may be drawn ~ack into the container. With time the bacteria originally present in the eye, both normal and pathological, will be permitted access to a medium which may-cause them to prolifer-ate. Thus, subsequent drops of medication may r~introduce to the eye either excessive levels of typically present bacteria, or large numbers of , .,. . ~

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pathogens. Neither situation is acceptable.
To cope with the problems of contamination, drug manufacturers often introduce an anti~bacterial agent to ~he drug container. In most cases, this agent or preservative can be very effective at sup-pressing the growth of bacterial contaminants within the container. Unfortunately, there exists a sig-nificant population of patients for whom these pre-servatives represen~ ocular irritants, or in more se~ere cases, cause allergic reactions. ~uch un-toward ocular reactions prevent such patients from using the drug in this kind of packaging. For these patients, single-use, non pres~rved drug packaging is a partial answer, but at si~nificantly increased cost and inconvenience.
Of course, similar problems are encountered with other drop administered medicines, for example, for the ear or nose.
Container contamination can also be the result of particulate matter being dxa~n back into the con-tainer with the liquid in the dropper tip that has not been delivered as a drop. C)ver several drop deliveries in, for example, dust:y conditions, a sig-nificant accumulation of dust in the container is possible. If the liquid to be dleliver~d needs to be ultrapure as, for example, in certain ~icroelec-tronic applications, such accumulation could raise a serious problem.

~low Rate Dosage of drugs administered as drops is regu-lated on the basis of the number of drops to be ap-plied. Formation of the drops is directly related to flow rate or metering of the liguid from the con-tainer. The drops themselves fall from the dropper . . . .

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tip when the weight of the pendant drop exceeds the surface tension forces holding th~ drop to the drop-per tip~ In the ideal case, each drop should be identical to the previous one. In practice, how-ever, other factors intervene to cause significantvariation i~ drop size. One of the most significant factors is the rate of drop formation. Some at-tempts to control drop size and uniformity by pre-cise control in manufacturing of tolerances of the dropper tip orifice have been somewhat successful.
However, such controls are difficult to achieve and increase manufacturing costs. Furthermore, in using . such devices, if the drop is formed rapidly, more liquid can be "injected" into the body of the drop as it is beginning to break free. The~e drops will be larger, and thus will carry more drug, than if the container is squeezed very slowly. In extreme circumstances, drug may be ejected in a steady stream, which renders control of dosage impossible.
While this is a minimal problem when the drugs are delivered by a trained professional, i~ becomes significant when the drugs are delivered by the pa-tie~ts themselves. The flow rate, which is directly related to the finger pressure while squeezing, can-not be easily controlled. ~he visual clue, that is, the growth of the drop itself, cannot be readily observed if the eye is about ~o receive the.same drop or if the dropper is not positioned in the line of sight in use.
The problem OI delivery control is not re-stricted to ophthalmic drugs, of course, and there is a clear need for controllable addition devices in a wide range of, for example, pharmaceutical dis-pensing applications.

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Description of the Invention In the metering device de~ined in the presen*
invention there is an inherently greater reisistance to liquid flow than in a metering device of the prior art. For this reason, it becomes most diffi-cult to produce a continuous stream of liquid by squeezing the container. This resistance to liquid flow-also tends to damp out the natural variations in s~uee~ing force that occur from momen~ to moment during use of a metering device of this ~ype. As a result, the sequential drops metered from such a device tend to have a much more uniform size.
It is therefore an object of this invention to provide a flow metering device in which the problems of contamination and uncontrolled flow rate are sub-stantially reduced.
It is a further object of this invention to provide a dropper for ocular medicines that is pro-tected from inadvertent bacteria:l contamination and thus permit a significan~ reduct:ion or the complete elimination of preservatives in the medicine.
It is another ob3ect of the invention to pro-vide a liquid metering and.dispensing device in which a liquid, surh as a medicine, is dispensed as substantially uniform drops.
The above objects are provided by a device for dispensing a liguid in drop form which comprises a container having a dropper tip including a passage-way for ingress of air to and egress of liquid from the device, the passageway communicating between the body of the container and an orifice, means for tem-porarily reducing the volume of the container and, disposed within the dropper tip, across, so as to intersect the passageway, and preferably adjacent : ~ .
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W092/09523 PCT/US90/07~29 the orifice thereof, a microporous membrane-with pores of a size to resist the passage of undesired contamination, the membrane having a liquophilic portion permitting delivery of metered drops of a S liquid to a desired lscation outside the container, and a liquophobic portion adapted to resist the pas-sage of such liquid but to permit the passage therethrough of air, the passageway communicating with both the liquophilic and liquophobic portions of the membrane.
The membrane is sealed to the inside surface of the dropper within the tip region so as to prevent the passage of liquid around, as opposed to through, the membrane.
The membrane comprises two components in side-by-side or juxtaposed relationship. One component has a lig~tophobic character, that is, it resists the passage of liquids. The other component has a liq-uophilic character, that is, liquids pass through it readily. Thus, liguids exiting the container ~hrough the porous membrane will pass exclusively through the liquophilic component: and will be re-jected by the liquophobic component. Liguids being suc~ed back into the container will pass exclusively through the liquophilic compon~nt. However, air will flow into the container to replace the expelled liguid, through the liquophobic side, displacing any liquid adhering to the walls of the passageway and causing the liquid to flow through the membrane and into the reserv~ir of the container.

The Container In use, the container functions as a reservoir ~or the liquid to be dispensed. It is provided with means to temporarily reduce its volume, typically by ,, .
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W092~09~23 PCT/US90~7029 -8- 2~ ~ 7 3 ~ ~
providing that at least part of the container is elastically deformable. Thus, pressure on a deform-able portion of the container will reduce the effec-tive volume and force the liquid contained therein out of the container when it is appropriately oriented.
A~ter a desired number of drops hav~ been ex-pelled from the container and the deforming pressure is removed, the liquid below the me~brane in the tip is drawn back into the container. It i~ preferred that this occurs as a continuous column, that is, no droplets should break away and be left behind in the tip area. Sl~oh droplets could be a hospitable enYi-ronment for baoterial growth and as such hould be avoided so far as possible. Making the passageway narrow helps to maintain a continuous column. Also, appropriate selection of the material from which the wall of the passageway is formed, so as to have a critical wetting surface tension matched to the sur-face tension of the liquid employed, enhancesdraining from the passageway as a continuous column.
Making the volume of the tip area very small helps to minimi2e the problem of retai,ned drops, generally. It is, therefore, pa:rticularly preferred that the volume between the orifice Gf the dropper and the surface of the composite me~brane be as small as possible. In particular, the volume of the tip of the dispenser (i.e., between the orifice and the membrane) is of a volume which is sufficiently small to ensure that all of the li~uid flows back to the membrane without air percolating past liquid in the tip. ~olumes of the order of from about 0.001 to a~out 0.15 cm3 are suitable and most preferred are volumes of from about 0.05 to about O.l cm3.
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provide membrane support by various means including, for example, a series of ribs on the inside surface of the dropper tip and/or an interior beading pro-viding a seating surface to ~hich the membrane can be bonded. Care should, however, be exercised to ensure that such support devices do not impede or distort the flow of metered drops from the device.
Support could also be provided by the provision of a transverse septum or bar that would help resist any tendency of the membrane to deform under pressure.

Wetting_of Porous Media The wettability or liquophilicity of a porous structure, e.g~, a membrane, is a function of that structure's critical wetting surface tension ~CWST) (discus~ed below) and the surface tension of the ap-plied liquid. If the CWST is at least as high as the surface tension of the liquid, the liquid will spontaneously wet the porous structure, which may be termed "liquophilic" with respect to that liquid.
Conversely, if the CWST is lower than the surface tension of the liquid then it will not be wet and will be liquophobic with respect to that liquid.
When a liquid is brought into contact with the upstream surface of a porous medium and a small pressure di~ferential is applied, flow into and through the porous medium may or may-not occur. A
condition in which no flow occurs is that in which the liquid does not wet the material of which the porous structure is made.
A series of liguids can be prepared, each with a surface tension about 3 dynes/cm higher compared with the o~e preceding. A drop of each may then be placed on a porous surface and ob~erved to determine whether it is absorbed quickly, or remains on tbe WO92/09523 ~CT/~9~/07029 ~7~

su.rface. ~or example, applying this technique to a 0.2 ~m porous polytetrafluoroethylene ~PTFE) mem-brane, instan~ wetting i5 o~served for a liquid with a surface tension of about 26 dynes/cm. However, the structure remains unwetted when a liquid with a surface tension of about 29 dynes~cm is applied.
Similar behavior is observed for porous media made using other synthetic resins, with the wet/
unwet values dependent principally on the surface lo charac~eristics of the material from which the porous medium is made and, secondarily, on the pore size characteris~ics of the porous medium. For ex-ample; fibrous polyester, specifically polybutylene terephthalate (hereinafter "PBT"~ sheets which have pore diameters less than about 20 ~m will be wetted by a liquid with a surface tension of about 50 dynes/cm, but will not be wettecl by a liquid with a surface tension of about si dynes~cm.
In order to characterize this behavior o~ a porous membrane, the term "criti~al wetting surface tension" (CWST) is defined as follows. The CWST of a porous medium may be determined by individually applying to its surface a series of liquids with surface tensions v~ryinq by about 2 to about 25 4 dynes/cm, and observing the absorption or non- :
absorption of each 1 iquid . ~he CWST of a porous medium9 in units of dynes~cm, is defined as the mean value of the surface tension of the liquid which is absorbed and ~hat of a liquid of neiqhboring surface tension which is not absorbed. Thus,-in the exam-ples of the two preceding paragraphs, ~he CWST's are about 27.5 and about 52 dynes/cm, respectively.
In measuring CWST, a series of standard liquids for testing is prepared with surface tensions vary-ing in a sequential manner by about 2 to about WO92~0gS23 PCT/~S90/07029 4 dynes/c~. Ten drops from each of at least two ofthe sequential surface tension standard liquids are independently placed on representative portions of the porous medium and allowed to stand for 10 min-utes~ Visual observation is made after lO minutes.Wetting is defined as absorption into the porou~
medium by at least nine of the ten drops within 10 minutes. Non-wetting is defined by non-absorption or non-wetting o~ at least nine of the ten drops in lO minutes. Testing is continued using liquids of successively higher or lower surface ten-sion, until a pair ha~ been identified, one wëtting and one non-wetting, which are the most closely spaced in surface tension. The CWST is ~hen within that range and, for ~onvenience, the average of the two surface tensions is used as a single number to specify the CWST.
A nu~ber of alternative methods for contacting porous media with liquids of sequentially varying surface tension can be expected to suggest them-selves to a person knowledgeable of physical chem-istry after reading the descript:ion above. One such involves floating a specimen on the surfaces of liq-uids of sequentially varying surface tension values, and observing for wet-through of the liquid or, if the fiber used is more dense than water, observing fox sinking or floating. Another means would clamp the test speciman in a suitable jig, followed by wetting with the test liquids while applying varying degxees of vacuum to the underside of the specimen.
Appropriate solutions with varying surface ten-sion can be prepared in a variety of ways; however, those used in the development o~ the product de~
scribed herein were:

W092/09523 PCT~U~90/07~29 Surface Tension Solution or fluid range, dynes/cm Sodium hydroxide in water 94 - 110 Calcium chloride in water gO - 94 Sodium nitrate in water 75 - 87 Pure water 72~4 Acetic acid in water 38 - 6g Ethanol in water 22 - 35 n-Hexane 18.4 FC77 (3M Corp.) 15 FC8~ (3~l Corp.) 13 Liquophilic Medium Suitable materials for the liquophilic medium include forms of polyamides, polyvinylidene fluo.-1~ ride or difluoride (PVDF), and cellulose compounds,such as nitrocellulose and mixed esters of cellulose, as well as glass ~i~er mats with suitable binders. Hydrophilic, microporous polyamide n!embranes, particularly nylon 66 membr~nes, and PVDF
membranes are especially preferr~3d.
A preferred microporous, hydrophilic nylon 66 membrane material having high binding.capacity, uni-formity, controlled pore siz~, and high surface area is BiodyneTM, available from Pall Corporation or one of the hydrophilic membranes described in U.S. Pat-ent 4,340,479, the subject matter of which i5 spe-cifically incorporated herein. This patent describes a polyamide resin, a microporous, . hydrophilic membrane formed from *he resin, and a method of forming the membrane. The membrane is a skinless alcohol-insoluble polyamide membrane having `
a ratio of CHz:NHCO of methyl~ne CH2 to amide NHCO
groups within a range of about 5:1 to about 7:1 and . ~ ` ' , : .
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W~92/09~23 PCT/VS90~07~29 has pores that are substantially uniform from surface to surface and a parti~le removal rating of about 0.1 ~M to about 5 ~M.
Another preferred membrane useful as the liquo-philic medium is the CARBOXYDYNE~ membrane, also available from Pall Corporation. CARBOXYDYNE~ is a hydrophilic, microporous, skinless nylon 66 membrane with controlled surfac~ properties formed by the co-casting process described in U.S. Patent ~,707,26~, also specifically incorporated herein. As discussed below, the process involves cocastiny a polyamide, such as the type described in U.S. Patent 4,3~0,479, preferably nylon 66, and a polymer containing an abundance of ionizable acidic groups, such as carboxyl groups, to form a membrane having controllecl surface properties characterized by carboxyl functional yroups at its surface. Besides being hydrophilic, these membranes have pore sizes from about 0.0~ to about 10 micrometers or more and in certain instances have modifi~ed zeta potentials (e.y., negative zeta potentials in acidic media).
They also have filtration effici~sncies ranging from molecular dimensions 6pyrogens) to particulates larger than the pore si~es.
Yet another preferred ~embrane use~ul as a ~edium for the liquophilic compound of the present invention is the Posidyne~ membrane, also available from Pall Corporation. Posidyne~ is a polyamide membrane which is similar to Carboxydyne~ and the media described in U.S. Patent 4,707,266, in both chemical and physical properties as well as in its method of manufacture. This and similar materials are described in U.S. Patent 4,702,840, specifically incorporated herein by refere~ce. While these materials are surface-modified, hydrophilic, W092/09523 PCT/U~0/07029 -14- 2~7321 mlcroporous, polyamide membranes, ike those described in U.S. Patent 4,707,266, they are charge-~odified to ha~e strongly positive zeta potentials in alkaline media rather than negative ~eta potentials. This results from the cationic, water-solu~le, quaternary a~monium, thermosetting polymers with which the polyamid~ resin is cocast during its manufacture. As the surface- and charge-modifying polymers, epoxy-functional polyamido/polyamino epichlorohydrin resins are preferred.
These hydrophilic, microporous, substantially alcohol-insoluble polyamide membranes with con-txolled surface properties are formed by cocasting an alcohol-insoluble polyamide resin with a water-soluble, me~brane-surface-modifying polymer having functional polar groups. Like the preferred hydro-philic, microporous ~ylon membranes which do not have controlled surface modified polar groups pres-ent, the polyamide membranes of the present inven-tion having controlled surface properties are alsoskinless; that is, they are characterized by through pores extending from surface to surface which are of substantially uniform size and shape.
Polyvinylidene fluoride memhranes are not in-herently water-wettable but can be rendered such by an appropriate surface modification. Terms such as "surface," "polymeric substrate surface," "membrane surface," or like terms, used in the singular or plural, are intended herein to inclu~e not only the gross surfaces, i.e., the external or outer sur-faces, such as those which are exposed to view, but also the internal surfaces or those surfaces which define the pores of the polymaric substrate or me-dium, that is, the substrate or membrane surface is that portion of the polymeric substrate or membrane .
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~' 92/09~23 PCT/U~0~0702g medium which is capable during use of being con-tacted by a fluid, particularly a liquid. The term "surface modification", or like terms, as used in describing surface-modified PVDF mambranes, refers specifically to changes in the "surface," described above, wh~rein chemical bonds are formed between the surface of the polymer being ~odified and suitable compound or compounds used to modify the polymer surface, rendering said surface modifications permanent, non-removable, and non-leachable.
~icroporous, polyvinylidene fluoride membran~s which have been surface modified to render them hydrophilic are commercially available. An'example of a suitable material is described by Joffee et al.
in U.S. Patent 4,774,132, q'Polyvinylidene Difluoride Structure," assigned to Pall Coxporation, and by Gsell et al. in a pending application, V.S. Serial No. 07/447,415, "Filtration Med;ia With -Low Protein Adsorbability," both specifically incorporated herein by reference.
~ he membranes described in U.S. Patent 4,774,132 include microporous PU'DF membranes which are ~urface-modified by having yrafted tbereto a polymer derived at least in part from polymeriza~le vinylic monomer, the modifying polymer including ~nctional groups sufficiently polar or ionic to provide the membrane with a critical surface energy of at least about 80 dynes/cm. The polymerizable vinylic monomer preferably includes at least one carbo~yl qroup, preferably conjugated with an ethylenically unsaturated bond. Most preferably the polymerizable vinylic monomer has the general formula~
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R- C- C - C - OR

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W0 92/OgS23 PCT/US90/07029 wherein R is H, an aminoalkyl or quaternized aminoalkyl group having l to 3 carbon atoms, or a hydroxyalkyl group having l to 3 carbon atoms; R~, R'l, and R~ independently are H , an alkyl group having l to 3 carbon atoms, a carboxyl group, a carboxyalkyl group having l to 3 carbon atoms, or a hydroxyalkoxycarbonyl group having l to 3 carbon atoms.
The method of making these membranes involves the steps of contacting a PVDF medium with an alkali solution, such as a potassium hydroxide soluti;on, to form activated sites on the surface of the medium.
The activated structure is then rinsed to remove residual alkalii and subsequently contacted with a solu~ion of a polymerization initiator, such as potassium peroxydisulfate, and the polymerizable vinylic monomer. The monomer is then pol~merized and grafted to the surface of th~e medium.
Gsell et al describe a porous polymeric PVDF
medium having a low affinity for amide group-containing materials formed fxom a PVD~ substrate and a surface-modifying polymeric material having a low a~finity for amide group-con1:aining materials formed n situ at and covalently bonded to the surface of the PVDF substrate. The surface-modifying polymeric material is ~erived from a monofunctional monomer, preferably unsaturated, which has at least one hydroxyl group~ for example, hydroxyalkyl acrylates and methacrylates.
As discussed above, wettability or liquophilic ity is a function of the CWST of the porous membrane and the surface tension of the liquid. Wettability may also be expressed in terms of intrusion pressure required for liquid to penetrate into the pores of the membrane. Membrane materials which are partic-''~ , , -' ' ~ ' . :' W~2/09523 PCr/US90/07029 ularly preferred have intrusion pressures of, or close to, zero for the liquids with which they are used.

Liquophobic Medium The term "liquophobic" as used herein is effec-tively the obverse of the term 7'1iquophilic", that is, a porous liquophobic material has a CWST lower than the surface tension of the applied liquid and is not readily or spontaneously wetted by the ap-plied liquid(s). Liquophobic materials are charac-terized, then, by a high contact angle hetween a drop of liquid placed on the surface and the sur-face. Such a high contact angle indicates poor wetting.
Another way of expressing the suitability of a material for use as the liguophobic component of the instant invention relates to the wetting resistance characteristics of the material,. A suitable mate~
rial should be capable of resisting a.liquid intru-sion pressure greater than the pressure that can be generated by manual squeezing oi. the dispensing bottle.
Suitable materials include polyolefins, such as pol~propylene, polyhalogenated polyolefins, particu-larly perfluorinated polyolefins, such as polytetra-fluoroethylene, and pol~vinylidene difluoride, as well as sulfones. Polytetrafluoroethylene is a pre-ferred polymer and unmodified, as well as surface modified polyvinylidene difluoride, particularly a fluoropolymer-grafted microporous polyvinylidene di~luoride membrane or similarly surface modified polyamides are most preferred. Methods of forming the fluoropolymer-grafted polyvinylidene difluoride as well as similarly surface modified polyamide~ are ' described by Degen et al. in U.S. Patent 4,~54,256, "Hydrophobic Membranes", incorporated herein by reference. More particularly, the fluoropolymer grafted polymers may be formed by contacting a microporous polymeric substrate or membrane with a solution of at least one polymerizable fluorine-containing monomer and exposing the membrane to ionizing radiation to produce a microporous hydrophobic polymeric membrane in which a hydrophobic fluoropolymer is chemically bonded to all the surfaces of the microporous membrane substrate. The surface-modi~ied membranes have CWST's of less than about 28 dynes/cm. Both polyamides and fluorine-containing polymers,`such as PVDF may be used as the substrate. The monomer contains an ethylenically unsaturated group and a fluoroalkyl group, the latter preferably being a perfluoroalkyl group.
The surface modifications described above for enhancing or creating a membrane of reduced CWST, also, as described earlier, are ~permanent, non-removable, and non-leachable because the modifying polymers are chemically bound to the substrates which they modify. This is in contrast to the conventional treatm~nt of normally liguophilic membranes by addition of liquophobic agents to the membrane or a section of the membrane, such as silicone vils or like compounds, which coat the membrane surfaces but are not chemically bound thereto, such as by covalent bonds. Such prior art surface treated membranes have the drawback that liquid contact with such treated surfaces can result in leaching of the liquophobic agents into the liq-uid to be delivered. There are several disadvan-tages to such leaching, including progressively .'. :

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W~92/~9~23 PCT/US9OtO7029 reduced liquophobicity of the treated membrane and simultan~ous contamination of the delivered liquid.
Such contamination is of particular concern in drops delivered to the sensitive tissues of the eye.

The Composite Membrane The composite membrane used in the present invention has both a liquophilic, preferably hydro~
philic, component and a li~uophobic, preferably hy-drvphobic, component. Most frequently, the edges of these media will be bonded together along the line of contact so as to form a single unit with ~he com-ponents in side-by-side or abutting (as opposed to face-to-face) relationship to one another. Part of the composite will be liquophilic with respect to the liquid to be dispensed with the device and the other part will be liquophobic with respect to that same liquid.
It is to be understood, however, that the term ~'composite membrane" is also intended to ~over the functional equivalent of such a membrane where the two components are not physical]Ly joined but act to close off separate but ad~acent exit passages from the device~ One example would be~provided ~y a de-vice wi~h a dropper tip havi~g a transverse septum or bar in the area of the dropper tip dividing the exit passageway effectively in two. with such a device each membrane could be sealed to the septum or bar and the inside ~all of the tip and there would be no need for bonding the two membranes to-gether. Indeed, this configuration might conferuseful support benefits for-the membranes.
The liquophilic and liquophobic membranes can be attached within the dropper tip by known tech-niques, such as heat welding or ultrasonic welding.

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After bonding the membranes, discs of the mem-brane pairs may be punched out using conventional die punching techni~ues. The position of the die above and below the bond line can be used to set the relative proportion of the liguophilic and liquopho-bic portions of the membranes.
After punching, the discs may be transferred to the ~a~e of the dropper tip and welded in position.
Alternatively, two separate regions of the dropper base may ~e def ined and individual components of the liquophilic and li~uophobic membranes welded thereto.
It is found that the bonding operation is often much si~plified if the substrate membrane of both the liquophilic and li~uoph~bic components is formed from the same basic materia1. This can be achieved by surface modification of chemically i~entical or closely related polymeric mem~ranes to give liquo-philic and liquophobic compon~nts which are then joined together to form the composite membranes useful in the device of the invention. Composite membranes in which both components are suitably .
. -.

W~g2/09523 PCT/US90/07029 surface-modified polyamides are particularly pre-ferred~ Also, composite membranes ~ormed from naturally hydrophobic polyvinylidene difluoride and its surface-modified counterpart ar~ preferred.
The liquophobic component of the membrane of the present invention typically has a CWST of less than about 35 dynes/cm and typically from about 20 dynes/cm to about 30 dynes/cm. By contrast, the liquophilic component of the membrane has a CWST of a~ leas~ about 50 dynes/cm, such as rom about 70 dynes/cm to about 100 dynes/cm, and preferably from about 72 dynes/cm to about 95 dynes/cm. ';
Both components of the membrane have a pore size adapted ~o resist passage of an undesired con- :
taminant. Most frequently, in tAe medicinal con-text, this will be bacterial contamination. In this context, for the liquophilic component, pore si~es of from about 0.04 to about 0.65 ~m are ~uitable.
Preferred are pore sizes of from about 0.01 to about 0.45 ~m and most preferred are pore sizes of from about 0.15 to about 0.2 ~m. ~he liquophobic compo-nent, however, ge~erally has a pore size of from about 0.01 to about 0.45 ~m with from about 0.04 to about 0.~ ~m preferred and ~rom ~ibout 0.1 to abou$
0.2 ~m most pref~rred. If particulate contamination is the main concern, the pore si~es can be redefined accordingly.
The surface area of the composite membrane can be divided between liquophilic and liquophobic com-ponants in any convenient proportion.. However, theproportion~ should be consistent with the functions that the components have to ~ulfill~ The liquo-philic membrane should be of such a size that the liquid wi~hin the container will be dispensed in drops at an appropriate rate. Too large an area .. :. , ' .

WO92~09523 PCT/US90/07029 ~7~

could result in a high rate of flow or even, in extreme cases, a stream of liquid. On the other hand, too small an area would result in a very low drop delivery rateO
It is preferred that the liquophilic and liquophobic components of the composite membrane be formed from the same polymeric material, the surface of the polymeric material of at least one of the components being permanently chemically modified.
10 Thus, a ma~erial which is inherently either liquophilic or liquophobic toward a particular solvent is permanently, chemically surface-modified to provide the material for the other of the liquophobic or liquophilic medium. Examples of particular combinations of such liquophilic and liguophobic components suitable as the composite membranes, i~ the order of preference, are the following:
a hydrophilic polyamid~3, such as BiodyneTM, and a surface-modified hydrophob:ic polyamide, such as that described in U.S. Patent 4,954,256;
. a hydrophilic polyamide, such as Posidyne~, and a surface-modi~iecl hydrophobic polyamide, such as that described in U.S. Patent 4,954,256;
a hydrophilic polyamide, such as Carboxydyne~, and a surface-modified hydrophobic polyamide, such as that dascribed in U.S. Patent 4,954,256;
a PVDF membrane, ~urface-modified to render it hydrophilic, such as that described in U.S. Patent 4,774,132 and an ~nmodified hydrophobic PVDF;
and a PVDF membrane, surface-modified ~o render it more hydrophobic (i.e. having a lower ~, ~

.

W~92/Og523 PCT/VS~0/07~29 3 2 ~

CWST), such as the mater~al described in U.S. Patent 4,954,25~.

Meteri~sLFunction of the Hvdrophilic Component An important aspect of the present invention is the provision of a deformable dropper bottle that meters out drops at a care~ully regulated flow rate.
The ~etering effect, i.e., the control of flow rate and uniformity of drop size, is determined by ~wo factors: the pore size and, as indicated above, the area, specifically the gross surface area. When the liquophilic portion of the membrane selected is hy-drophilic with respect to the liquid (i.e., water) to be dispensed and has a porosity that is fine enough to exclude bacteria, the factor that most lS affects the rate at which drops are dispensed is the gross surface area (i.e., the external or outer surfaces, such as those exposed to view) of tha liquophilic, preferably hydrophilic, portion of the membrane. Thus, drop formation rate is largely indePendent of the pressure differentials caused by any defoxmations of the dropper bottle likely to be encounter~d in the normal use of such devices. This is, of course, a significant safety factor since the dropper bottle, by design and intent, will be for use by medically untrained people with varying interpretations of the level of pressure needed to express one drop from the bottle.
The liquophilic, preferably hydrophilic, mem-brane surface area that is best suited to produce an appropriate liquid flow rate in the above circum-stances is found to be about-from about 20 mm2 to about 90 mmZ, and preferably from about 40 mm2 to about 50 mm2.
Th~ liquophobic, preferably hydrophobic, com-.

W092J09523 PCT/US90/~7029 ~t7 ponent should be large enough ~o accommodate rela-tively easy but controlled access of air to replace the liquid dispensed. It is ~ound that, with devices of the size normally employed for eye drop-pers, satisfactory results may be obtained when theproportion of the liquophilic component is from about 50 to about 70% of the total gross surface area of the composite membrane. This provides suf-ficient surface area of the liquophilic, preferably hydrophilic, component to ensure a satisfactory flow rate from the dropper bottle when it is d.eformed.
Particularly preferred,.however, are membranes;where about 60 to about 70% of the gross surface area is provided by ~he liquophilic component. I~ is recog-nized, however, that some applications may requireproportions outside the above xanges.

Description of the Drawinqs Figure 1 is a diagrammatic cross-section of the .tip and adjacent portions of a deformable container according to the invention.
Figure 2 is a plan view of the microporous mem-brane shown separate from the containex.

Description of Preferred Embodiments The invention is further described with spe-cific reference to the drawings which illustrate a preferred embodiment of the invention. In the draw-ings, Figure 1 xepresents a partial cross-section of a dropper according to the invention. Figure 2 rep-resents a plan vi w of a composite membrane accord-ing to the invention.
In Figure 1, a container tpartially shown in .
:. ~. . ; . : .
, i, ., : . ,.
~ ""., ,. .' ~

W092/09523 P~T~US90/07029 dotted outline as 1) has a dropper tip portion or a cap 2 which includes a passageway 7 that exte~ds from the upstream or inlet side of a dispensing cap (or outlet end of the container body where the tip S portion and container body are of unitary construc-tion) and which terminates in an orifice 3. Dis-posed in the dropper tip 2, across and intersecting the passageway 7 adjacent the container is a membrane 4 sealed to the surface of the dropper tip 2. Tbe membrane 4 has a generally circular configuration conforming to the dimensions of the opening in the dropper tip 2. The membrane 4 is a composite of two components in side-by-side relationship: a liquophilic component 5 and a liguophobic component 6 sealed at their line of contact to form a unitary disc-shaped composite mem-brane. In use, the container is inverted, that is to say, placed with its dropper tip downwards, and squeezed. ~his reduces the effective volume of the container and creates a pressure differential between the inside and the outside of the container such that the liguid contained therein is expelled.
The ligui~ is typically a drug in an aqueous solu-tion intended for treatment of eye disorders. The 2S drug solution wets and then passes through the liq-uophilic membrane into the dropper tip. As the pressure is maintained, the liquid emerges from the dropper tip orifice and begins to form a pendant drop. When used for administering ocular medicine, it is intended that this drop fall in~o the eye of the patient. ~s the drop reaches critical size, it breaks away from the dropper tip ori~ice and falls into the eye. When the squeezing pressure on the container is removed, a differential pressure is created between the outside of the container and the ' WO92/09~23 PCTtUS90~07~29 2~7 32~

inside, as the elastic walls of the container at-tempt to return to their original shape. This dif-ferential pressure causes the liquid remaining in the dropper tip to be drawn back towards the inside of ~he container. In doing so, the liquid must pass through the liquophilic component of the membrane.
~he dropper tip is designed so that substantially all if not all of the liquid remaining after the drop is dispensed is drawn back into the container.
As the retreating liquid/air interface in the drop-per tip reaches the liquophilic membrane, flow through thP liquophilic memhrane halts. This is because significantly higher pressure than is avail-able from recovery of the elastically deformèd walls of the container, which reverses the pressure dif-ferential referred to above, is required to drive air through the wetted li~uophilic membrane. Incom-ing air, however, is necessary to compensate for the volume of the drug dispensed. This can enter the container through the adjacent liquophobic membrane.
Thus, sufficient air will enter t:he container via the liquophobic membrane to equalize the pressure inside and out.
In the event that the liquid in the dropper tip has become contaminated, for example, by contact with bacteria from the patient's optical fluids, the bacterial component is filtered by the liquophilic component as the rest of the liquid is drawn back into the container. Thus, liquid and air re-entering the container from the dropper tip area arefiltered free of bacterial contamination.
Since the internal volume and shape of the dropper tip are selected to mini~ize the possibility of any retained liquid, any bacteria present and trapped on the liquophilic and liquophobic membrane .:
, :, ., ;,.,. . :

WO 9~/09523 PC~/US9O/n7029 components are thus exposed to the air. Such expo-sure may inhibit growth such that subsequent drops dispensed from the container will be either free or substantially free of contaminants previously en-trained in the dropper tip. Thus, the tip will bereturned substantially to its pre-contamination state with each cycle ~f use. If contamination is likely to have occurred and it is imperative that no amount of bacteria be returned to the eye, then the first drop or drops o~ drug may be discarded so as to purge the tip. Experiments in which the dropper has been seeded with known levels of bacteria sug-gest that this procedure is effective.

ExDeriment,al Data To test the concept, two dropper bottles and tips were constructed using a 0.2 ~m rated ~iodyne nylon 66 membrane as the liquophilic segment, and 0.02 ~m rated polytetrafluoroethylene membrane as the liquophobic segment. The membranes were first bonded together along theîr midlines using a Branson ul~rasonic welder with a gold booster and a flat 2" x 2" welding horn. An approximately 1 to 3 mm overlap was ~ormed at the weld l:ine. The dropper tips were modified by ~illing the excess space between the membrane and the tip with an epoxy compound, resulting in a volume of approximately 0.1 cm3. Discs were then cut from the resulting composite strip and ultrasonically welded at their perimeters to the base of the dropper tips. In these tips approximately 60~ of the total membrane area was occupied by the liq~ophilic membrane.
The tips were then aseptically in~erted into dropper bottles containing an ophthalmic drug timo-lol maleate, but with no preservatives included.

, 2~7 ~1 A solution containing approximately l x lO5 per milliliter of ~. aeuriqinosa was prepared. sottle l was oriented tip upright, squeezed, and held. Then, an aliquot of lO0 ~l of the E _gr~llgurs~ solution was injected into the opening of the dropper tip us-ing a microsyringe. The pressure on the bottle was then released, and the lOO ~l ali~uot was observed ~o draw ~ack into the bottle. The secsnd bottle, bo~tle C, did not have any bacteria solution in-jected and was kept as a control.
Ten minutes after the inoculation of bottle l,a sequence of 4 drops of timolol maleate was squeezed out and each drop directed to fall into a quadrant of an agar plate (Ql to Q4). Each drop was then spread by streaking across the quadrant with a stexile loop. one day later, ~he same procedure was repeated with another agar plate. This r~petitive sampling was continued for 14 days. In parallel, the control ~ottle, bottle C, was sampled in the identical manner.
The data for the inoculated bottle, bottle 1, is shown below:

COLONIES~OUADRANT
DAY Q~ 02 03 04 10 min 128 90 6~ 51 ls~ O O ~ O
2nd o o o 0 3rd o 120a o 0 4th to 14th O 0 0 0 a Note: colonies seen were not p. aeuroqinosa.

The control bottle, bottle C, had zero counts for all days in all quadrants.

:: ;, .

WO92~09~23 PCT/US9OtO7029 In this experiment, the lOo ~1 inoculation was observed to be drawn back into the bottle. Thus, the bacteria in the aliquot was presented to the composite membrane at the bas~ of the dropper tip.
Lack of p. aeuriainosa growth in the samples from days 1 to 14 demonstrates that none of the bacterial challenge reached the contents of the bo~tle.
The data from the ~ drop se~uence taken 10 min-utes after inoculation is a confirmation that ~
aeuriginosa bacteria was present in the dropper tip and, in addition, that it would not flourish or could be purged by the removal of several drops.
In the discussion of the preferred-embodiment illustrated in the drawings, a device adapted to dispense ocular medicine was taken as the paradigm.
It is to be understood, however, that the device of the invention could be used for other purposes in which it is convenient to dispense the medicine in the form of drops such as, for example, medicine for - 20 the ears or the nose. In genera:l, the medicine will be made up in an aqueous or saline solution; thus the terms liquophilic and liquophobic will most con-veniently imply hydrophilic and hydrophobic, respec-tively. It is understood, however, that occasion-ally medicines are made up in a light oil and thus the broadest interpretation of liquophobi~ and liq uophilic must embrace the use of such liquids as media for the appli ation of the medicine.
The body of the container is provided with means for temporarily reducing the volume of ~he container. Typically, this will be by providing that at least part of the walls of the container are elastically deformable. Thus, squeezing the con-tainer will temporarily reduce its volume. Alterna tive means such as a movable plunger or an inflat-, ' " ' ~ ` ~

~.

WO92/~9~23 ~ PCT~US90/07029 able insert in the container could be devised but are not generally preferred over the simplicity of the squeezable container.

,, ,., ,.:, ~ :~ .

, - .~

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A device for dispensing liquids in drop form which comprises a container having a dropper tip including a passageway for ingress of air to and egress of liquid from said device, said passageway communicating between the container and an orifice in the dropper tip; means for temporarily reducing the volume of the container; and a microporous composite membrane with pores of a size to resist passage of contaminants, said membrane having a liquophilic component permitting delivery of drops of a liquid to a desired location outside the container and a liquophobic component adapted to.
resist the passage of such liquid but to permit the passage therethrough of air, said composite membrane disposed across said passageway, said passageway being intersected by said membrane and communicating with both the liquophilic and liquophobic components, said liquophilic and said liquophobic components being formed from the same material, the surface of at least one of said liquophilic and liquophobic components being permanently chemically modified.

2. A device according to claim 1 wherein the pore size of the liquophilic component of the membrane is from about 0.04 to about 0.65 µm.

3. A device according to claim l wherein the liquophilic component comprises from about 50 to about 70% of the gross surface area of the membrane.

4. A device according to claim 1 wherein the volume between the composite membrane and the dropper tip orifice is from about 0.001 to about 0.15 cm3.

5. A device according to claim 1 wherein the liquophobic component has a critical wetting surface tension of less than about 35 dynes/cm.

6. A device according to claim 5 wherein the liquophilic component of the composite membrane has a critical wetting surface tension of at least about 72 dynes/cm.

7. A device according to claim 1 wherein the liquophilic component is made from a surface-modified microporous polyamide membrane.

8. A device according to claim 1 wherein said liquophobic component is made from a polyamide membrane surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

9. A device according to claim 7 wherein said liquophobic component is made from a polyamide membrane surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

10. A device according to claim 1 wherein said liquophobic component is made from polyvinylidene difluoride.

11. A device according to claim 1 wherein said liquophilic component comprises polyvinylidene difluoride, surface-modified to render it hydrophilic.

12. A device according to claim 10 wherein said liquophilic component comprises polyvinylidene difluoride, surface-modified to render it hydrophilic.

13. A device according to claim 1 wherein said liquophobic component comprises polyvinylidene difluoride, surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

14. A device according to claim 11 wherein said liquophobic component comprises polyvinylidene difluoride, surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

15. A device according to claim 1 wherein the container has elastically deformable sides and is deformable by squeezing.

16. A device according to claim 1 wherein the porosity of the microporous membrane is suitable for resisting the passage of bacterial contamination and the hydrophilic component has a gross-surface area of from about 20 mm2 to about 90 mm2.

17. A device according to claim l wherein the CWST of said liquophilic component is at least about 72 dynes/cm and said liquophobic component is less than about 28 dynes/cm.

18. A device according to claim 1 wherein said orifice comprises a single orifice.

19. A device according to claim l wherein said liquophilic and liquophobic components are arranged in juxtaposed relationship.

20. A device according to claim l in which said composite microporous membrane has liquophilic and liquophobic components bonded together in side-by-side relationship, the liquophilic component having a surface area of from about 20 mm2 to about 90 mm2, an average pore size of from about 0.15 to about 0.25 µm, and a CWST of at least about 72 dynes/cm; and the liquophobic component having a CWST of less than about 28 dynes/cm and having an average pore size of from about 0.1 to about 0.2 µm.

21. A device according to claim 20 wherein said composite membrane comprises a polyamide.

22. A device according to claim 20 wherein said composite membrane comprises polyvinylidene difluoride.

23. A dispensing cap for use with a container for dispensing liquids in drop form, the cap comprising a dropper tip including a passageway for ingress of air to and egress of liquid from the container, said passageway communicating between the container and an orifice in the dropper tip; and a microporous composite membrane with pores of a size to resist passage of contaminants and having a liquophilic component permitting delivery of drops of a liquid to a desired location outside the container and a liquophobic component adapted to resist the passage of such liquid but to permit the passage therethrough of air, said composite membrane disposed across said passageway, said passageway being intersected by said membrane and communicating with both the liquophilic and liquophobic components, said liquophilic and said liquophobic components being formed from the same material, the surface of at least one of said liquophilic and liquophobic components being permanently chemically modified.

24. A dispensing cap according to claim 23 wherein the pore size of the liquophilic component of the membrane is from about 0.04 to about 0.65 µm.

25. A dispensing cap according to claim 24 wherein the liquophilic component comprises from about 50 to about 70% of the gross surface area of the membrane.

26. A device according to claim 23 wherein the volume between the composite membrane and the dropper tip orifice is from about 0.001 to about 0.15 cm3.

27. A dispensing cap according to claim 23 wherein the liquophobic component has a critical wetting surface tension of less than about 35 dynes/cm.

28. A dispensing cap according to claim 23 wherein the liquophilic component of the composite membrane has a critical wetting surface tension of at least about 72 dynes/cm.

29. A dispensing cap according to claim 23 wherein the liquophilic component is made from a surface-modified microporous polyamide membrane.

30. A dispensing cap according to claim 23 wherein said liquophobic component is made from a polyamide membrane surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

31. A dispensing cap according to claim 29 wherein said liquophobic component is made from a polyamide membrane surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

32. A dispensing cap according to claim 23 wherein said liquophobic component is made from polyvinylidene difluoride.

33. A dispensing cap according to claim 23 wherein said liquophilic component comprises polyvinylidene difluoride, surface-modified to render it hydrophilic.

34. A dispensing cap according to claim 32 wherein said liquophilic component comprises polyvinylidene difluoride, surface-modified to render it hydrophilic.

35. A dispensing cap according to claim 23 wherein said liquophobic component comprises polyvinylidene difluoride, surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

36. A dispensing cap according to claim 33 wherein said liquophobic component comprises polyvinylidene difluoride, surface-modified to have a critical wetting surface tension of less than about 28 dynes/cm.

37. A dispensing cap according to claim 23 wherein the porosity of the microporous membrane is suitable for resisting the passage of bacterial contamination and the hydrophilic component has a gross surface area of from about 20 mm2 to about 90 mm2.

38. A dispensing cap according to claim 23 wherein the CWST of said liquophilic component is at least about 72 dynes/cm and said liquophobic component is less than about 28 dynes/cm.

39. A dispensing cap according to claim 23 wherein said orifice comprises a single orifice.

40. A dispensing cap according to claim 23 wherein said liquophilic and liquophobic components are arranged in juxtaposed relationship.

41. A dispensing cap according to claim 23 in which said composite microporous membrane has liquophilic and liquophobic components bonded together in side-by-side relationship, the liquophilic component having a surface area of from about 20 mm2 to about 90 mm2, an average pore size of from about 0.15 to about 0.25 µm, and a CWST of at least about 72 dynes/cm; and the liquophobic component having a CWST of less than about 28 dynes/cm and having an average pore size of from about 0.1 to about 0.2 µm.

42. A device according to claim 41 wherein said composite membrane comprises a polyamide.

43. A device according to claim 41 wherein said composite membranè comprises polyvinylidene difluoride.