CA1142831A - Osmotically driven fluid dispenser - Google Patents

Abstract

ABSTRACT
An improved version of an osmotically driven minipump that is used to administer drug solutions is disclosed. The basic components of the improved minipump are: an inner flexible bag that holds the drug solution; a plug having a recessed inner end that seals the bag opening;
a solution filling/discharge port through the plug; a cup-shaped, thermoformed sleeve that fits partly about the bag and is made from a dispersion of an osmotically effective solute in a water soluble, thermoplastic polymer vehicle; a shape-retaining, semipermeable membrane that encapsulates the bag-sleeve subassembly; and a flow moderator that is received through the filling/discharge port in the plug.

Description

The invention relates to improvements and modifications of an osmotically driven fluid dispenser.
The invention is an improvement in the osmotically driven dis-pensers described in commonly owned United Sta~es Patent No. 3,987,790, United States Patent No. 3,995~631 and United States Patent No. 4,034,756.
Therefore, these patents are believed to be relevant prior art, particularly the minipump described in these patents. The minipump's components are an inner flexible bag that holds the drug charge, an intermediate layer of an osmotically effective solute composition, such as an inorganic salt, that encapsulates the bag, an outer shape-retaining membrane that is at least in part permeable to ~ater and that encapsulates both the layer of osmotically effective solute composition and the bag, a plug that seals the open end of the bag, and a filling/discha~ge port that communicates with the interior of the bag.
In operation the bag is filled with drug solution via the filling/
discharge port and placed in an aqueous environment, such as a body cavity or trithin body tissue. Water is imbibed from the environment by the osmoti-cally effective solute through the membrane into the space between the inner flexible bag and the membrane. Since the bag is flexible and the membrane is rigid, the imbibed water squeezes the bag inwardly, thereby displacing drug out the filling/discharge port.
Minipumps of the above described structure and operation perform ~ell but are not beyond being improved. Two shortcomings of the minipump are: ~1) the layer of osmotically effective solute is applied by dipping the inner bag into a suspension of an osmotically active solute, ~Yhich is a highly lahor intensive process, and ~2~ uniformity and reliability of ~ .

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the thickness of the solute layer are difficult to assure in large scale production due to the inherent variability of the dipping process. The first shortcoming afects the ease and cost of production. The second shortcoming affects the average release rate of drug, the constancy of the release rate, and the duration of release. The present invention is direc-ted toward eliminating or reducing these shortcomings.
The invention is an osmotically driven fluid dispenser comprising an inner flexible bag adapted to contain the fluid, an intermediate layer of an osmotically effective solute composition at least partly encapsulating the bag, an outer shape-retaining membrane encapsulating the layer of osmotically effective solute composition~ said membrane being at least in part permeable to water, and a port that extends from the interior of the bag to the exterior of the dispenser through which the fluid may be charged into the bag and dispensed from the bag, characterized in that the layer of the osmotically effective solute composition ls in the form of a thermo-formed sleeve comprising a dispersion of 50% to 75% by weight osmotically effective solute in 25% to 50% by weight water soluble thermoplastic polymer vehicle.
In the drawings:
Figure 1 is an elevational, exploded, sectional view of one embodiment of the dispenser of the invention;
Figure ~ is an enlarged sectional view of the dispenser of Figure l; and Figure 3 is a sectional view of the dispenser for Figure 1 taken along line 3-3 of Figure 2.
Like numerals refer to like parts in the various figures.

The drawings illustrate an osmotically driven fluid dispenser, generally designated 11. As shown in Figure 1, the basic components of dispenser 11 are an outer, shape-retaining semipermeable membrane 12, an intermediate thermoformed sleeve 13 made from a dispersion of an osmoti-cally effective solute in a water soluble, thermoplastic polymer vehicle ~matrix), an inner flexi.ble bag 14, a plug 15, a flow moderator 16, and a flow moderator cap 17.
Bag 14 is adapted to contain a fluid composition, such as an active agent composition 18 ~Figure 2) in fluid form. The term "active agent" as used herein means any compound or mixture of compounds that can be dispensed to produce a predetermined beneficial and useful result.
Active agents include pesticides, germicides, biocides, algicides, rodenti-cides, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservating agents, surfactants, disinfectants, sterilization agents, catalysts, chemical reactants, fermentation agents, cosmetics, foods, nutrients, food supplements, drugs, vitamins, sex sterilants, fertility inhibitors, fertility promoters, air purifiers, microorganism attenuators, and other compositions that benefit the environ-ment, surroundings, and habitat, including animals and humans. In the preferred embodiment the active agent is a drug that produces a local or systemic physiologic or pharmacologic response when administered to animals or humans.
In order to be a suitable container for the fluid, bag 14 should be substantially impermeable to the fluid composition and be compa-tible ~ith the composition. By "compatible", it is meant that the bag should not be corroded7 solubilized, or otherwise affected deleteriously by the composition. Additionally, when the composition is a drug, the composition should not be signific~ntl~ contaminated by the bag, such as by the extraction of leachables from the material forming the bag. Bag 14 may be made from elastomeric compostions that may be formed into thin sheets.
The elastomeric properties of the elastomeric composition and the thickness of the bag wall should be such as to cause the bag to readily collapse in~ardly when a force is applied to the bag exterior. Such elastomeric compositions are disclosed in commonly owned United States Pat. No.
3,760,984 at col. 5, line 40 to col. 7, line 37 and in commonly o~ned United States Patent No. 3,995,631 at col. 8, lines 14-32.
Bag 14 is elongated and generally cylindrical and is closed at its end 19 and open at its opposite end 22. Its wall is thickened outwardly at 23 to form a shoulder 24. As seen in Figure 2 the portion of the exterior af bag 14 below shoulder 24 is encapsulated by sleeve 13 whose wall is approximately as thick as shoulder 24 is wide.
Sleeve 13 is made from a thermoformable osmotically effective solute composition. The components of the composition are an osmotically effective solute and a water soluble, thermop:Lastic polymer vehicle. The purpose of the solute is to imbibe ~ater from the environment across mem-brane 12 into the space between the exterior of bag 14 and the inner surface of membrane 12, that is, the space occupied by sleeve 13. The osmotic pres-sure of the solute when in solution should be sig~ificantly greater than the osmotic pressure of the liquid of the environment. In dispensers that are to be ingested by or placed ~ithin an animal, the osmotic pressure of the solute solution must exceed the osmotic pressure of body fluids (about 750 kRa~. Osmotically effective solutes that may be used in sleeve 13 are dis-clos~ed in United States Pat. No. 3,760,~84 at col. 7, line 38 to col. 8, ~l~4~

line 2 and in United States Pat. No. 3,9~5,631 at p. 11~ line 65 to col. 12, line 3 and col. 14, lines 20-28. Sodium chloride is an especially effective osmotic solute in that the osmotic pressure of sodium chloride is sufficient-ly high to remove the dependence of pumping rate on the osmotic pressure of the surrounding environment. Sodium chloride is efficient in salting out the polymer vehicle so that the influence of binder does not enter into the performance of the dispenser, and the dispenser is less imposing than those containing other salts on the surrounding biological environment.
The polymer vehicle serves to make the osmotically effective composition thermoformable. Depending upon its osmotic pressure in solution it may also contribute to the osmotic effectiveness of the composition. The vehicle functions as a matrix in which the osmotically effective solute is dispersed, and renders the composition flowable upon application of heat and pressure. A preferred vehicle is a mixture of 40% to 70% by weight poly ~ethylene oxide) having a molecular ~eight in the range of 100,000 to 4,000,000 and 30% to 60% by weight poly~ethylene glycol) having a molecular weight in the range of 1,000 and 30,000.
The thermoformability of the composition permits sleeve 13 to be produced by conventional thermoforming techniques such as compression mold-ing, injection molding, or extrusion. Because of this, sleeve 13 may be made as a module in large quantities with a high degree of thickness repro-ducibility With sleeve 13 in modular form the assembly of dispenser 11 is simplified. Furthermore~ the subassembly composed of bag 14 and sleeve 13 is not as fragile as the solute coated bags of prior versions of the minipump. Thus the subassemblies are less likely to be damaged in the coating process by wllicïl membrane 12 is applied to the subassembly.

In addition ~o the solute and vehicle the osmotically effective solute composition may contain minor amounts of other materials such as fillers, pigments, lubricants~ and other conventional additives that facilitate thermoforming.
Sleeve 13 i5 encapsulated by outer membrane 12. Membrane 12 also covers the exterior of the portion of bag 14 above shoulder 24 and fornls a fluid tight seal therewith. At least a part of membrane 12 is permeable to water. Membrane 12 is impermeable to the osmotically effec-tive solute composition. Membrane 12 is also shape-retaining, ~hat is, it is sufficiently rigid to be substantially undeformed by -the hydrostatic pressure that is generated in the space between its inner surface and the cxterior of bag 14 by the water imbibed by the solute of sleeve 13. The thickness and composition of membrane 12 affect the rate at which water will be imbibed through it by the solute in sleeve 13. Such membranes and CQmpositions that may be used to form them include cellulose acetates, cellulose acetate butyrates, and other shape-retaining semipermeable mem-branes including those disclosed in said United States Pat. No. 3,760,984 at col. 4~ line 53 to col. 5, line 39 and in said Uni*ed States Pat. No.
3,995,631 at col. 7, line 40 to col. 8, line 15.
Plug 15 fits into the open end 22 of bag 14. Plug 15 is general-ly cylindrical and is approximately as long as the thickened portion of bag 14 above shoulder 24. The exterior of plug 15 forms a fluid tight seal wi~h the portion of the interior surface of bag 14 with which it is in contact.
Plug 15 has an axial, central bore 25 extending completely through it. Bore 25 provides access to the interior of bag 14 for filling bag 14 wi*h active agent composition 18. Bore 25 is also adapted to receive flow moderator 16.

Plug 15 has a hemispherically shaped recess 26 in its inner (bottom) end 27. The presence of such a racess or concavity in end 27 reduces the likelihood of entrapping air in bag 14 when filling bag 14 with composition 18 In prior versions of the minipump this plug has been generally cylin-drical in shape, its inner end joining the wall of the bag at a 90 angle.
During the filling of the bagJ the fluid has a natural tendency, due to its high surface tension, to form a curved surface beginning near the top of the wall of the bag and continuing up to the filling/discharge port. This curvature causes an air pocket at the intersection of the wall of the bag and the plug. Plug 15 has a hemispherically recessed lower surface, curved to substantially match the arc created by the surface tension of the drug solution during the filling process. This configuration reduces the volume of the dispenser which cannot be filled due to air entrapment from approxi-mately 15% to less than 2% to 3%. Plug 15 may be made from the same materials as are used to make flexible bag 14; however, the dimensions of plug 15 should be such that it is substantially inflexible.
Flo~ moderator 16 provides the passageway rom the interior of bag 14~to the exterior of dispenser 11 by which composition 18 is discharged ~rom dispenser 11. Flow moderator 16 comprises a conduit, in the form of a rigid cylindrical tube 28, and a dome-shaped head 29. Tube 24 and head 29 may be made from suitable plastics or metals. Head 29 has an axial, thread-ed bore 32 that receives threaded end 33 of tube 28. As shown in Pigures 1 and 2, end 33 extends outwardly from the spherical surface of head 29 to provide a site for attaching an external catheter tube (not shown) in the event dispenser 11 is to be used to administer composition 18 to a remote location. Tne outer diameter of tube 28 is approximately the same as the diameter of bore 25 such that tube 28 may be inserted through bore 25 into bag 14 ~ith tube 28 fitting snugly within bore 25 so as to form an essentially fluid ~ight seal ~ith plug 15. The length of tube 28 is such that it extends into bag 14 to at least about 50% Or the elongated dimen-sion of the interior of bag 14, i.e., the distance from the inner side of end 19 to end 27 of plug 15. Preferably tube 28 extends into bag 14 over substantially the entire, but not all of ~say 85% to 95%), of said elonga-ted dimension. The inner diameter of tube 28 is correlated to the length o tube 28 such that substantial diffusional flow of composition 18 through tube 28 will not occur. Tube 28 is, in efect, a capillary that provides ~esistance to the flow of composition 18, thereby reducing or eliminating bulk loss of composition 18, from the outlet port of dispenser 11. Head 29 has a diameter slightly less than the outer diameter of plug 15. As seen in Figure 2, the flat side of head 29 fits against the top of plug 15.
Dispenser 11 may be filled with fluid 18 via bore 25 of plug 15.
For instance, the needle of a fluid loaded syringe may be inserted through bore 25 and the syringe's contents discharged into bag 14. To insure that a predetermined fluid pumping rate is achieved, it is desirable to complete-ly~fill bag 14 with fluid 18. After the bag is filled, tube 28 of flow moderator 16 is inserted through bore 25 to the position shown in Figure

2. As described above, tube 28 functions as a capillary and inhibits loss of fluid 18 from the dispenser even though it is subjected to substantial movement or tipped upside down. Dispenser 11 operates in the following manner. Once placed in aqueous environment, such as within a body cavity ~ ~ithin body tissue, water from the environment is imbibed by the solute of sleeve 13 through membrane 12 at a rate determined b~ the osmotic activity of the solute, and the osmotic reflectlon coefficient, composi-tion, thickness, and area of membrane 12. The imbibed water causes the volume of the space between the inner surface of membrane 12 and the exterior of bag 14 (the space initially occupied by sleeve 13) to increase.
~Id since membrane 12 is shape-retaining, the imbibed water generates hydraulic pressure on the exterior of bag 14 causing bag 14 to be squeezed int~ardly. This squeezing forces fluid 18 through tube 28 and out of the dispenser.
As indicated~ fluid 18 may be an active agent composition. In such instances the dispenser 11 will, of course, discharge active agent directly. Alternatively, fluid 1~ may be inert and the dispenser may be used simply as a displacement pump. In this alternative the dispenser ~ill, of course, have to be suitably interconnected by well known means to a reservoir of the fluid ~active agent) to be discharged, such that the inert fluid displaces the fluid from the reservoir in a predetermined regimen to the desired administration site. Such alternatives are partic-ularly attractive in instances in which the fluid to be discharged is incompatible ~ith bag 14.
Flow moderator cap 17 may be used to cover protruding end 33 of tube 29 ~hen dispenser 11 is used ~ithout an external catheter tube connec-tion. Cap 17 is crescent-shaped and has an axial threaded bore 34 that receives end 33 of tube 29. The curvature of its concave underside 35 matches the convexity of the top surface of head 29 so that the former fits tightly against the latter ~Figure 2). The outer diameter of cap 17 is the same as the outer diameter of membrane 12. Thus the hemispherical exterior of cap 17 provides a smooth blunt surface that aligns with the ~5a3~L
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exterior surface of membrane 12.
The components o dispenser 11 may be made and assembled as follows. Bag 14 and sleeve 13 are thermoformed, such as by injection molding, by known teclmiques. The bag-sleeve subassembly may be made using solvent or adhesive bonding, depending on the material involvcd. If ~ag 14 and sleeve 13 are capable of being solvent bonded, bag 14 is dipped in the mutual solvent and inserted into sleeve 13. When the subassembly is put together by adhesive bonding, bag 14 is dipped into an appropriate adhesive and then inserted into sleeve 13. Membrane 12 may be applied to the bag-sleeve subassembly by dipping it in a solution of membrane material as taught in United S*ates Pat. No. 3,987,790 a~ col. 4, line 63 or membrane 12 may be coated onto the subassembly using conventional coating equipment and techniques such as pan coating and fluidized spray coating.
The ollo~ing example is intended to further illustrate the a~oYe described dispenser and its manuacture. ~his example is not inten-ded to limit the invention in anr wa~.
Example C~lindrical flexible bags ~.50 cm long, 4.01 mm I.D. and 4.62 ~ Q~ ~er~ ~nject~on molded at 176C, 3.5 x 103 kPa, from an elastomeric 20 ~ ~ styxene-butadiene copolymer ~sold under the trade designation, Kraton 2104).
Osmotic sleeves ~ere prepared for each dispenser as follows.
The components (64.5wt% NaCl, 20 wt% poly~ethrlene oxide), molecular wt 600~000, 15 wt% pol~eth~lene glycol~ of molecular we ght 20,000 and 0.5 ~t% colloidal SiO2, sold under the trade name Cabosil) were bulk blended a HQbaxt mixex for 20 minutes at low speed. ~he homogenous powder ~lend ~as pressed into 0.6 cm tablets capable of being gravit~ fed into ~e~ r~h~

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Arborg injection molding eqwipment. The osmotic sleeves (2.21 cm long, 4,87 mm I~D~, and 5.89 mm O.D.) ~ere formed from the tablets br injection molding at 149C, 6.5 x 103 kPa.
C~lindrical plugs of the above described styrenebutadiene CQ~oly~er were injection molded. The plugs were 0.5 cm long, had a 4.1 mm Q~n " and their louer surfaces were recessed hemispherically ~o a depth of 1~37 mm. Each had a central axial bore 0.76 mm in diameter through its entire length~ ;
The cylindrical flexible bags were dipped into a 15 wt% cyclo-hexane solution of the st~rene-butadiene copolymer mentioned above and ~exe inserted into the osmotic sleeve. The arcuate surfaces of the plugs ~ere coated with a glue bead of 15 wt% crclohexane solution of the copoly-~er and a plug ~as inserted into the open end of each of the bags. A 22 gauge needle was inserted through the bore of each plug and the plugged bags~ere placed in an oven at 40C for 2 hours.
~n outer se~ipermeable membrane uas applied to the dispensers b~ coating w~th a ~urster coater. ~he membrane was a 4 wt% methylene ~hlQride solution of cellulose acetate butyrate ~sold under the designation A E~astman Kodak~381-2~. ~he coating was applied to a thickness of 0.38 mm.
~e dis~ensers ~ere t~en oven-dried at 55C for about 5-10 days.
Flau moderators were prepared for each dispenser as follows.
~enty~one gauge needle stock ua~ cut into Z.36 cm lengths. Each length qf tubing ~as circumferentially grooved with 15 grooves, equally spaced Q,3 mm apart along one end of the tube, such that a 4.3 mm distance begin-n~ng at one end of the tube i~ grooved. Caps uere insert molded around the ~xaQved portion of t~e tube 3 mm fxom the grooved end, from styreneacrrlon-~e~ r ~,4~J~7,sa~

itrile copolymer. The caps ~ere hemisphe~ical, 5.6 mm in diameter, ~ith a Q.8 mm diameter diametrical ~ore. Hemispherical overcaps had a 6.5 mm O~D~, ~ere 4.3 mm in length with the bottom hemispherically recessed to a depth of 1.3 mm, had a 0.8 mm diameter diametrical bore through the length o~ the overcap, and ~ere injection molded from ethylene-vinyl-acetate copolymer. The overcaps ~ere pressed onto the 3 mm grooved exten-s~n of the tube.

Claims (4)

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

1. An osmotically driven fluid dispenser comprising an inner flexible bag adapted to contain the fluid, an intermediate layer of an osmotically effective solute composition at least partly encapsulating the bag, an outer, shape-retaining membrane encapsulating the layer of osmotically effective solute composition, said membrane being at least in part permeable to water, and a port that extends from the interior of the bag to the exterior of the dispenser through which the fluid may be charged into the bag and dispensed from the bag, characterized in that the layer of the osmotically effective solute composition is in the form of a thermoformed sleeve comprising a dispersion of 50% to 75% by weight osmotically effective solute, in 25% to 50% by weight water soluble ther-moplastic polymer vehicle.

2. The dispenser of claim 1 further characterized in that the osmotically effective solute constitutes 60% to 70% by weight of the dis-persion and the polymer vehicle constitutes 30% to 40% by weight of the dispersion.

3. The dispenser of claim 1 further characterized in that the polymer vehicle comprises 40% to 70% by weight poly(ethylene oxide) having a molecular weight in the range of 100,000 to 4,000,000 and 30% to 60% by weight poly(ethylene glycol) having a molecular weight in the range of 1,000 to 30,000.

4. The dispenser of claim 1 further characterized in that the osmotically effective solute is sodium chloride and the vehicle consists of a mixture of poly(ethylene oxide) of approximately 600,000 molecular weight, poly(ethylene glycol) of approximately 20,000 molecular weight, and colloidal silicon dioxide.