CA1053108A - Osmotically driven fluid dispenser - Google Patents
Osmotically driven fluid dispenserInfo
- Publication number
- CA1053108A CA1053108A CA261,892A CA261892A CA1053108A CA 1053108 A CA1053108 A CA 1053108A CA 261892 A CA261892 A CA 261892A CA 1053108 A CA1053108 A CA 1053108A
- Authority
- CA
- Canada
- Prior art keywords
- bag
- dispenser
- fluid
- exterior
- plug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
Abstract
PATENT APPLICATION OF ALZA CORPORATION
ALZA FILE NO.: ARC 491 TITLE: OSMOTICALLY DRIVEN FLUID DISPENSER
ABSTRACT OF THE DISCLOSURE
An osmotically driven fluid dispenser that is capable of being miniaturized and used as an implant to administer fluid drug compositions to animals and humans.
The dispenser comprises a flexible inner bag adapted to contain the drug composition, a fluid tight plug fitted into the bag opening, a port in the plug through which the composition may be charged to the bag, an intermediate layer of an osmotically effective solute composition partly cover-ing the bag exterior such that a band of the bag exterior proximate to the plugged end is not covered by the layer, an outer shape-retaining semipermeable membrane covering the layer of solute and forming a fluid tight seal at said band, and a tube that fits snugly through the port in the plug and extends substantially into the interior of the bag after the drug composition is charged to the bag, said tube providing an outlet through which the drug composition may be dispensed.
ALZA FILE NO.: ARC 491 TITLE: OSMOTICALLY DRIVEN FLUID DISPENSER
ABSTRACT OF THE DISCLOSURE
An osmotically driven fluid dispenser that is capable of being miniaturized and used as an implant to administer fluid drug compositions to animals and humans.
The dispenser comprises a flexible inner bag adapted to contain the drug composition, a fluid tight plug fitted into the bag opening, a port in the plug through which the composition may be charged to the bag, an intermediate layer of an osmotically effective solute composition partly cover-ing the bag exterior such that a band of the bag exterior proximate to the plugged end is not covered by the layer, an outer shape-retaining semipermeable membrane covering the layer of solute and forming a fluid tight seal at said band, and a tube that fits snugly through the port in the plug and extends substantially into the interior of the bag after the drug composition is charged to the bag, said tube providing an outlet through which the drug composition may be dispensed.
Description
I ARC ~191 ~ 3~
1 I BACKGI~OUN~ OF T~lE INVEI~TION
1 I BACKGI~OUN~ OF T~lE INVEI~TION
2 ~
1 The invention is an improvement in the osmotically
1 The invention is an improvement in the osmotically
3 ¦ driven dispensers descrLbed in commonly owned Canadian S ¦ Patent No. 956~609.
1 The dispenser referred to therein as the "minipump" is espec-; 7 ¦ ially relevant. The minipump is an osmotically driven dispenser ¦ whose size makes it especially useful as a therapeutic system l for administering drugs to anirnals and humans. Its basic com-91 ponents are an inner flexible bag that holds the drug charge, 10 ¦ an intermediate layer of an osmotically effective solute com-121 position, such as an inorganic salt, that encapsulates the bag, ¦ an outer shape-retaining membrane that is permeable to water 131 and that encapsulates both the layer of osmotically effective 14¦ solute composition and the bag, and a filling/discharge port 151 that communicates with the interior of the bag.
16¦ In operation the bag is filled with drug via the 171 filling/discharge port and placed in an aqueous environment, ¦ such as a body cavity or within body tissue. Water is imbibed 19¦ from the environment by the osmotically effective solute through 20 1 the membrane into the space between the inner flexible bag and 21 ¦ the membrane. Since the bag is flexible and the membrane is 22 ¦ riyid, the imbibed water squeezes the bag inwardly thereby 24 ~ displacing drug out the filling/discharye port.
¦ I~r~C 491 ,,~
1 ~iinipumps of the above dcscribed structure and oper-2 ation perform well but are not beyond being improved. Two 3 shortcomings of those dispensers are, (1) they tend to lose
1 The dispenser referred to therein as the "minipump" is espec-; 7 ¦ ially relevant. The minipump is an osmotically driven dispenser ¦ whose size makes it especially useful as a therapeutic system l for administering drugs to anirnals and humans. Its basic com-91 ponents are an inner flexible bag that holds the drug charge, 10 ¦ an intermediate layer of an osmotically effective solute com-121 position, such as an inorganic salt, that encapsulates the bag, ¦ an outer shape-retaining membrane that is permeable to water 131 and that encapsulates both the layer of osmotically effective 14¦ solute composition and the bag, and a filling/discharge port 151 that communicates with the interior of the bag.
16¦ In operation the bag is filled with drug via the 171 filling/discharge port and placed in an aqueous environment, ¦ such as a body cavity or within body tissue. Water is imbibed 19¦ from the environment by the osmotically effective solute through 20 1 the membrane into the space between the inner flexible bag and 21 ¦ the membrane. Since the bag is flexible and the membrane is 22 ¦ riyid, the imbibed water squeezes the bag inwardly thereby 24 ~ displacing drug out the filling/discharye port.
¦ I~r~C 491 ,,~
1 ~iinipumps of the above dcscribed structure and oper-2 ation perform well but are not beyond being improved. Two 3 shortcomings of those dispensers are, (1) they tend to lose
4 drug in bulk through the filling/discharge port, especially ~ when the dispenser is placed in an environment that experiences 6 significant movement, and (2) air bubbles trapped in the bag 7 during filling tend to completely or partially plug the filling/
8 discharge port. The former shortcoming affects the constancy 9 of the dosage rate adversely and may cause overdosing. The latter shortcoming may temporarily stop the dispensing or cause 11 the dosage rate to be erratic or unpredictable. The present 12 invention is directed towards eliminating or reducing both of 13 these shortcomings.
STATEMENT OF THE INVENTION
~6 17 The invention is an osmotically driven fluid d-ispenser ]8 comprising an elongated flexible inner bag closed at one end 19 and open at the other end and adapted to contain the fluid, a fluid tight plug fitted into the open end of the bag, a port 21 in the plug that provides a passageway from the interior of 22 the bag to the exterior of the dispenser through which the 23 fluid may be charged into the bag, an intermediate layer of 24 an osmotically effective solute composition covering the ex-terior of the bag, and an outer shape-retaining semipermeable .. . - - ~ : . ..
~nc .1 9 1 ¦
i3~
¦ membran~ covering the intermediate layer of osmotically effec-2 I tive solute composition, characterized in that- the osmotically 3 ¦ effective solute composition only partly covers the exter.ior 4 ¦ of the bag such that a band of the bag exter:ior proximate to : 5 ¦ the open end of the bag is not covered by the layer; the mem-61 brane forms a fluid tight seal with -the exterior of the bag at 7 ¦ said band; and the dispenser includes a conduit that fits snugly B ¦ through the port and extends into the interior of the bag after ~ 9 1 the fluid is charged to the bag, to provide an outlet through lO¦ which fluid may be dispensed from the bag under pressure.
: ,21 BRIEF DESCRIPTIOM OF T~]E DRAWINGS
: 131 : 14¦ In the drawings:
: 15¦ Figure l is an elevational, exploded, partly sectional 16¦ view of one embodiment of the dispenser of the invention;
~: 17¦ Figure 2 is an enlarged, sectional view of the dis-~ 18¦ penser of Figure l;
.~ 19¦ Figure 3 is an enlarged, elevational, partl~ sectional 20¦ view of another embodiment of the dispenser of the invention; an 21¦ Figure 4 is an enlarged, top plan view of the flow 22¦ moderator of the dispenser of Figure l~
: 231 Like numerals refers to like parts in the various : 241 flgures.
~ 251 '~ 261 ~7 ~81 3( ',, I . , , .., . .
~P~C ~91 ~ ~3g~8 I _E~AILED DE:scRIprrloN-oF Tl]E INVENTION
3 Figures 1 and 2 illustrate an osmotically driven 4 fluid dispenser, generally desiynated 11~ The basic components S of dispenser 11 are an outer, shape-retain.ing, sernipermeable 6 membrane 12, an intermed.iate layer 13 of an osootically effec-7 tive solute~ an inner flexible bag 14, a pluq 15, and a flow 8 moderator, generally designated 16.
g Bag 14 is adapted to contain a fluid composition, such as an active agent composition 17 (Fig. 2) in fluid form.
11 The term "active agent" as used herein means any compound or 12 mixture o: compounds that can be d.ispensed to produce a pre-13 determined beneficial and useful result. Active agents .include 14 pesticides, germicides, biocides, algicides, rodent.icides, fung.i-l~ cides, insecticides, antioxidants, plant growth promoters, plant 16 growth inhibitors, preservating agents, surfactants, disinfec-17 tants, sterilization agents~ catalysts, chemical reactants, 18 fermentation agents, cosmetics, foods, nutrients, food supple-19 ments, drugs, vitamins~ sex sterilants, fertility inhibitors, fertility promotors, air pur.if.iers, microorganism attenuators, 21 and other compos.itions that benefit the environment, surround-22 ings, and habitat .including ani.mals and humans~ In the pre-23 ferred embodiment the active agent is a drug that produces 24 a local or systemic phys.iological or pharmacological response when administered to animals or humans.
8 discharge port. The former shortcoming affects the constancy 9 of the dosage rate adversely and may cause overdosing. The latter shortcoming may temporarily stop the dispensing or cause 11 the dosage rate to be erratic or unpredictable. The present 12 invention is directed towards eliminating or reducing both of 13 these shortcomings.
STATEMENT OF THE INVENTION
~6 17 The invention is an osmotically driven fluid d-ispenser ]8 comprising an elongated flexible inner bag closed at one end 19 and open at the other end and adapted to contain the fluid, a fluid tight plug fitted into the open end of the bag, a port 21 in the plug that provides a passageway from the interior of 22 the bag to the exterior of the dispenser through which the 23 fluid may be charged into the bag, an intermediate layer of 24 an osmotically effective solute composition covering the ex-terior of the bag, and an outer shape-retaining semipermeable .. . - - ~ : . ..
~nc .1 9 1 ¦
i3~
¦ membran~ covering the intermediate layer of osmotically effec-2 I tive solute composition, characterized in that- the osmotically 3 ¦ effective solute composition only partly covers the exter.ior 4 ¦ of the bag such that a band of the bag exter:ior proximate to : 5 ¦ the open end of the bag is not covered by the layer; the mem-61 brane forms a fluid tight seal with -the exterior of the bag at 7 ¦ said band; and the dispenser includes a conduit that fits snugly B ¦ through the port and extends into the interior of the bag after ~ 9 1 the fluid is charged to the bag, to provide an outlet through lO¦ which fluid may be dispensed from the bag under pressure.
: ,21 BRIEF DESCRIPTIOM OF T~]E DRAWINGS
: 131 : 14¦ In the drawings:
: 15¦ Figure l is an elevational, exploded, partly sectional 16¦ view of one embodiment of the dispenser of the invention;
~: 17¦ Figure 2 is an enlarged, sectional view of the dis-~ 18¦ penser of Figure l;
.~ 19¦ Figure 3 is an enlarged, elevational, partl~ sectional 20¦ view of another embodiment of the dispenser of the invention; an 21¦ Figure 4 is an enlarged, top plan view of the flow 22¦ moderator of the dispenser of Figure l~
: 231 Like numerals refers to like parts in the various : 241 flgures.
~ 251 '~ 261 ~7 ~81 3( ',, I . , , .., . .
~P~C ~91 ~ ~3g~8 I _E~AILED DE:scRIprrloN-oF Tl]E INVENTION
3 Figures 1 and 2 illustrate an osmotically driven 4 fluid dispenser, generally desiynated 11~ The basic components S of dispenser 11 are an outer, shape-retain.ing, sernipermeable 6 membrane 12, an intermed.iate layer 13 of an osootically effec-7 tive solute~ an inner flexible bag 14, a pluq 15, and a flow 8 moderator, generally designated 16.
g Bag 14 is adapted to contain a fluid composition, such as an active agent composition 17 (Fig. 2) in fluid form.
11 The term "active agent" as used herein means any compound or 12 mixture o: compounds that can be d.ispensed to produce a pre-13 determined beneficial and useful result. Active agents .include 14 pesticides, germicides, biocides, algicides, rodent.icides, fung.i-l~ cides, insecticides, antioxidants, plant growth promoters, plant 16 growth inhibitors, preservating agents, surfactants, disinfec-17 tants, sterilization agents~ catalysts, chemical reactants, 18 fermentation agents, cosmetics, foods, nutrients, food supple-19 ments, drugs, vitamins~ sex sterilants, fertility inhibitors, fertility promotors, air pur.if.iers, microorganism attenuators, 21 and other compos.itions that benefit the environment, surround-22 ings, and habitat .including ani.mals and humans~ In the pre-23 ferred embodiment the active agent is a drug that produces 24 a local or systemic phys.iological or pharmacological response when administered to animals or humans.
-5-~C 4~1 ~ (~53~
.
1 In order to bc a suitable container for the fluid, 2 the bag should be substantially impermeable to the composition 3 and be compatible with the compos:it;on. By "compatible", Lt 4 is meant that the bag should not be corroded, solubilized/ or S otherwise affected deleteriously by the composition. Addition-
.
1 In order to bc a suitable container for the fluid, 2 the bag should be substantially impermeable to the composition 3 and be compatible with the compos:it;on. By "compatible", Lt 4 is meant that the bag should not be corroded, solubilized/ or S otherwise affected deleteriously by the composition. Addition-
6 ally, when the composition .is a drug or the like, the composi-
7 tion should not be sign.ificantly contaminated by the bag, such
8 as by the extraction of leachables from the material forming
9 the bag. Bag 14 may be made from elastomer.ic compositions that may be formed into thin sheets. The elastomeric proper-11 ties of the bag composition and the thickness of the bag wall l2 should be such as to permit the bag to readily collapse inwardly 13 when a force is applied to the bag exterior.
14 Bag 14 is elongated and generally cyl:indrical and is closed at its end 18 and open at its oppos.ite end 19. As seen .
16 in E'ig. 2, bag 14 is partly encapsulated by the layer 13 of ar.
17 osmotically effective solute composition such that a band 22 of the exterior of bag 14 proximate to open end 19 is not covered 19 by layer 13. The purpose of layer 13 is to imbibe water across membrane 12 into the space between the exterior of bag l4 and 21 the inner surface of membrane 12, that is, the space occup.ied 22 by layer 13. Osmotically effective solute compositions that 23 may be used to form layer 13 are disclosed in sa.id Canadian 24 Patent No. 956,609.
.
27 .
~ C ~91 ~ 3 1 ¦ L,ayer 13 is in turn encaps~lated by outer membrane 2 ¦ 12. ~embrane 12 also covers band 22 and forms a fluid tight 3 ¦ seal therewith. At least a part of membrane 12 is permeable 4 ¦ to water. Preferably all of membrane 12 is permeable to water~
5 ¦ Membrane 12 is impermeable to the osmotically ef~ective solute 6 ¦ composition~ Membrane 12 is also shape-retaining, that is, it 7 ¦ is sufficiently rigid to be substantially undeformed by the 81 hydrostatic pressure that is generated in the space between.its 9¦ inner surface and the exterior of bag 14 by the water imbibed
14 Bag 14 is elongated and generally cyl:indrical and is closed at its end 18 and open at its oppos.ite end 19. As seen .
16 in E'ig. 2, bag 14 is partly encapsulated by the layer 13 of ar.
17 osmotically effective solute composition such that a band 22 of the exterior of bag 14 proximate to open end 19 is not covered 19 by layer 13. The purpose of layer 13 is to imbibe water across membrane 12 into the space between the exterior of bag l4 and 21 the inner surface of membrane 12, that is, the space occup.ied 22 by layer 13. Osmotically effective solute compositions that 23 may be used to form layer 13 are disclosed in sa.id Canadian 24 Patent No. 956,609.
.
27 .
~ C ~91 ~ 3 1 ¦ L,ayer 13 is in turn encaps~lated by outer membrane 2 ¦ 12. ~embrane 12 also covers band 22 and forms a fluid tight 3 ¦ seal therewith. At least a part of membrane 12 is permeable 4 ¦ to water. Preferably all of membrane 12 is permeable to water~
5 ¦ Membrane 12 is impermeable to the osmotically ef~ective solute 6 ¦ composition~ Membrane 12 is also shape-retaining, that is, it 7 ¦ is sufficiently rigid to be substantially undeformed by the 81 hydrostatic pressure that is generated in the space between.its 9¦ inner surface and the exterior of bag 14 by the water imbibed
10¦ by layer 13, The th:ickness and composition of membeane 12
11¦ affect the rate at which water will be imbibed through it by ,21 layer 13.
13¦ Plug 15 fits into the open end 19 of bag 14. Plug 15 ~ 14¦ is generally cylindrical and is approximately as long as band ~ IS¦ 22. The exterior of plug 15 forms a fluid tight seal with . 61 the portion of the interior surface of bag 14 with which it .' i71 is in contact. Plug 14 has an axial, central bore 23 extending ,81 completely through it. Bore 23 provides access to the interior of bag 14 for filling bag 14 with composition 17. Bore 23 is also adapted to receive flow moderator 16. Plug 15 may be made 21 from the same materials as are used to make flexible bag 1~;
:. 22 however, the d.irnens.ions of plug 15 should be such that it is 23 substant:ially inflexible.
Flow moderator 16 provides the passageway from the interior of bag 14 to the exter.ior of dispenser 11 by which 2~ _7_ 33l ¦ ~RC ~9l ~0~3~8 1 composition 17 is dischaLged from dispenser ].1. Flow moderato~
2 lG comprises a conc~uit, in the form of a rigid cylindrical 3 tube 24, and a head or cap 25. Tube 24 and head 25 may be made from suitable plastics or metals, respectively. The outer diameter of tube 24 is approximately the same as the diameter of bore 23 such that tube 24 may be inserted through bore 23 7 into bag 1~ with tube 24 fitting snugly w;thin bore 23 so as . ~ to form an essentially fluid tight seal with pluy 15. The :- 9 length of tube 24 is such that it extends into bag 14 to at least about 50% of the elongated dimension of the interior 11 of bag 14, i.e., the distance from the inner side of end 18
13¦ Plug 15 fits into the open end 19 of bag 14. Plug 15 ~ 14¦ is generally cylindrical and is approximately as long as band ~ IS¦ 22. The exterior of plug 15 forms a fluid tight seal with . 61 the portion of the interior surface of bag 14 with which it .' i71 is in contact. Plug 14 has an axial, central bore 23 extending ,81 completely through it. Bore 23 provides access to the interior of bag 14 for filling bag 14 with composition 17. Bore 23 is also adapted to receive flow moderator 16. Plug 15 may be made 21 from the same materials as are used to make flexible bag 1~;
:. 22 however, the d.irnens.ions of plug 15 should be such that it is 23 substant:ially inflexible.
Flow moderator 16 provides the passageway from the interior of bag 14 to the exter.ior of dispenser 11 by which 2~ _7_ 33l ¦ ~RC ~9l ~0~3~8 1 composition 17 is dischaLged from dispenser ].1. Flow moderato~
2 lG comprises a conc~uit, in the form of a rigid cylindrical 3 tube 24, and a head or cap 25. Tube 24 and head 25 may be made from suitable plastics or metals, respectively. The outer diameter of tube 24 is approximately the same as the diameter of bore 23 such that tube 24 may be inserted through bore 23 7 into bag 1~ with tube 24 fitting snugly w;thin bore 23 so as . ~ to form an essentially fluid tight seal with pluy 15. The :- 9 length of tube 24 is such that it extends into bag 14 to at least about 50% of the elongated dimension of the interior 11 of bag 14, i.e., the distance from the inner side of end 18
12 to the inner end of plug 15. Preferably tube 24 extends into
13 bag 14 over substantially the entire, but not all of (say 85%
14 to 95%), of said elongated dimension~ The inner diameter of . - 15 tube 24 is correlated to the length of tube 24 such that sub-16 stantia~ d:iffusional flow of composition 17 through tube 24 17 will not occur. Tube 24 is, in effect, a capillary that pro-18 vides resistance to the flow of composition 17, thereby reducing 19 or eliminating bulk loss of composition 17 from the outlet port of dispenser 11. Althou~h not shown in the drawings, tube 24 ~ 21 may extend outwardly from the exter.ior of head 25 to provide 22 a site for attachment of a catheter or other dispensing means.
23 Head 25 ls hemispher.ical and has a diameter approximately equal 24 to the outer diameter of dispenser 11. It also has a diamet-: 25 r.ical bore 26 for receiving tube 24. As seen .in Fig. 2, the ` 27 ` 32 ! ~c ~91 I
I ¦ flat side o head 25 fits against the top of plug 15 and the 2 ¦ top edge of bag 14. Thus the spherical surface of head 25 3 ¦ provides a smooth blunt surface that generally alLgns with 4 ¦ the exterior surface of the bag-solute layer~membrane assembly, S ¦ which bluntness and alignment are important if the d.ispenser 6 ¦ is to be used as an implant to adm.inister drugs to an.imals or 7 ¦ humans. Referring to Fig. 4, head 25 has three radial, equi-8 ¦ spaced grooves 27 in its spherical surface that intersect at 9¦ bore 26. The outer end of tube 24 is inset sl;ghtly from the 10¦ spherical surface of head 25 (Fig. 2) and thus grooves 27 11¦ serve as flow channels for composition 17 exiting from the 12¦ outer end of tube 24.
13¦ Fig. 3 illustrates an osmotic dispenser, generally 14¦ designated 28 that is identical to dispenser 11 except in one ¦ respect, namely outer membrane 12 encapsulates the top edge of .
16¦ bag 14 and the top of plug 15 as well as the arcuate surfaces 17 of layer 13 and band 22. As discussed below, this difference 18 is caused by a difference in the techniques by which the mem-brane 12 is applied to dispensers 11 and 28. Like dispenser 11, dispenser 2~ also consists of an outer, shape-reta.in.ing, semi-21 permeable membrane 12, an intermed:iate layer 13 of an osmoticall~ , 22 effective solute, an inner flexible bag 14 adapted to contain a 23 fluid 17, a plug 15, and a flow moderator 16. These components 24 are of identical structure, composition, and interelationship as their like numbered counterparts of dispenser 11 except for 26 the single difference mentioned above.
27 .
_9_ 3l ~2 : . : : ~ . :
~J~C ~91 1 Th~ components of di~p~nser 11 may be made and 2 assemble~l as follows. Bag 14 may be injection molded from 3 suitable polymer compositions by known techniques. Bag 14 4 is then pla~ed on a support means, such as a mandrel, and a suspension of the osmotically effective solute in an appro-6 priate suspending medium is prepared~ The supported bag 14 7 is then dipped repeatedly in the suspension to the desired 8 depth, with intervening drying periods, until a layer 13 of 9 desired thickness is formed. A solution of membrane material is then made and the supported, solute coated bag 1~ is dipped 11 repeatedly into the solution to a depth just above the top 12 edge of bag 14, with intervening drying periods, until a mem 13 brane 12 of desired thickness is formed. The mandrel is then 14 removed and plug 15, which may be injection molded by known techniques, is glued into the open end o~ bag 14~ Head 25 16 may be machined by known techniques if it is metal, or injec-17 tion molded by known techniques if made from a synthetic poly-18 mer. The end of tube 24 may be affixed within bore 26 by 19 press-fittingr gluing, or other known techniques.
Dispenser 28 may be assembled as ollows~ A solute 21 coated bag 14 is made as in the case of dispenser 11. Plu~
22 15 is then fixed in place in the open end of bag 14 as in the case of dispenser 11. Membrane 12 of dispenser 28 is 24 then applied to the solute coated, plugged bag 14 by air s~spension-solution coating techn;ques in a Wurster coating 2~
3() -10-I ~C~lgl ;i3~
1 ¦ apparatus. Such apparatus and techniques are ~ell known.
2 ¦ This manner of ormin~ mernbrane 12 encapsulates the entire 3 ¦ bag-solute layer-plug assembly. Accordingly, a hole must 4 ¦ be formed through membrane 12 to bore 23 of plug 15. This S ¦ may be done by drilling, punching, or equivalent techniques.
6 ¦ Dispensers 11 and 2~ may be filled with fluid 17 7 I via bore 23 of plug 15. For instance, the needle of a fluid B¦ loaded syringe may be inserted through bore 23 and the syr-9¦ inge's contents discharged into bag 14~ To insure that a 10¦ predetermined fluid pumping rate is ach;eved, it is desirable 11¦ to completely fill bag 14 with fluid 17. After the bag is ,21 filled, tube 24 of flow moderator 16 is inserted through bore 13¦ 23 to the position shown in Figs. 2 and 3. As described 14 above tube 24 functions as a capillary and inhibits loss of fluid 17 from the dispensers even though they are subjected 16 to substantial movement or tipped upside down.
17 Dispensers 11 and 28 operate in the following manner.
l8 Once placed in an aqueous environment, such as within a body 19 cavity or within body tissue, water from the environment i5 imbibed by layer 13 through membrane 12 at a rate determined 21 by the osmotic activity of the osmotically efEective solute, 22 and the osmotic reflection coefficient, composition, thickness, 23 and area of membrane 12. The imbibed water causes the volume 24 of the space between the inner surface of membrane 12 and the 26 exterior of bag 14 (the space initially occupied by layer 13) 29 -11~
: -l to increase. And since membrane 12 is shape-retaining, the 2 im~ibed water generates hydraulic pressure on the exterior of 3 bag 14 causing bag 14 to be squeezed inwardly. This squeezing 4 forces fluid 17 through tube 24 and out of the dispenser. Any air bubbles that were trapped within bag 14 dur~ing filling 6 will tend to be located adjacent to the inner end of plug 15 7 or the inner surface of baq 14, depending on the attitude of 8 the dispenser. Therefore, these air bubbles are not likely 9 to block the entrance to tube 24 and interrupt or impede the flow of fluid 17 therethrough.
l1 As indicated, fluid 17 may be an active agent com-12 position. In such instances the dispensers 11 or 28 will, of 13 course, discharge active agent directly. Alternatively, fluid 14 17 may be inert and the dispenser may be used simply as a IS displacement pump. In this alternative the dispenser will, 16 of course, have to be suitably interconnected to a reservoir 17 of the fluid (active agent) to be discharged, such that the 18 inert fluid displaces the fluid from the reservoir in a pre-l9 determlned regimen to the desired administration site. Such alternatives are particularly attractive in instances in which 22 ~ the fluid t e discharged is lncompatible with ba9 14.
2~ -12-:
I\RC 491 ~05~
EXAMPLES
2 ___ .
The following examples are intended to further illus-4 trate the above described dispensers and their manufacture.
These examples are not intended to limit the invention in any 6 way. Unless indicated otherwise, percentages and parts are 7 by weight.
9 Example l Cylindrical flexible bags (2.33 cm long, 3.81 mm 11 inner diameter, and 4.67 mm outer diameter) were injection molded at 180~C, 77-84 kg/cm 2 from an elastomeric styrene-131 butadiene copolymer (sold under the trade designation, Kraton 14¦ 2104). A mandrel was inserted into each bag and mandrel sup-~51 ported bags were attached to a dipping platform.
16¦ A suspension of potassium sulfate particles in 17¦ dioxane-cellulose acetate solution (50 wt %) was prepared 18¦ and the mandrel supported bags were dipped into the suspen-191 sion to a depth of 1.8 cm 4 times for 1 min. per dip with 201 an intervening 15 min. room air drying period. This dipping 21¦ coated the bags with an approx;mately 0.3 mm thick coating 221 of the suspension.
231 A solution of cellulose acetate (sold under the 241 trade designation, Eastman E-398~10) in acetone (15 wt %) 251 was prepared and the mandrel-supported, potassium sulfate ,' 261 `12!71 . . .
- 31 . .
32 .
.~ , ,.... , . . ' ' :, . , ,:. ., . :
~ AI~C 431~
~ S3~
1 I coatcd bags werc dipp~cl completely in the svlution 20 times 2 ¦ for 1 min. per dip with an intervening 15 min. drying period.
3 ¦ Following this dipping the bags were oven dried at 60C for 4 1 15 days. This dipping formed a cellulose acetate mernbrane S ¦ approximately 0.65 mm thick about the entire bag exterior, ¦ including the potassium sulfate coated portion thereof.
7 I Cylindrical plugs of the above described styrene~
B¦ butadiene copolymer were injection moldedO The plugs were -9¦ 0.5 cm long, had a 3.9 mm outer diameter, and had a central axial bore 0.76 mm in diarneter. The arcuate surfaces of the 11¦ plugs were coated with a glue bead of a 20 wt % cyclohexane 121 solution of the copolymer and the plugs were inserted into 13¦ the open ends of the potassium sulfate-cellulose acetate coated 14¦ bags. A 22 gauge needle was ;nserted through the bore of each ~sl plug and the plugged bags were placed in an oven at 60C for 16¦ 2 hr.
17¦ Flow moderators were prepared for each dispenser as 18¦ follows Head or cap members were injection molded from styrene-191 acrylonitrile copolymer. The heads were generally hemispherical 20¦ 6.6 mm in diameter with a 0.8 mm diameter dlametrical bore. The 21¦ arcuate surface of the heads had three equispaced grooves that 22¦ intersected the bore. Twenty-one gauge needles were cut in 15 m~
231 lengths, blunted, inserted into the heads and glued in place 2~1 therein with an epoxy resin.
': 2sl .
: 26 ::' 27 :, ' ~ A~C 491 I ~S33L~D~
1¦ Example 2 21 Inner bags were made and coated with potassium sulfate 31 as described in Example 1. Plugs Eor the potassium sulfate 41 coated bags were made and glued into the open ends of the bags 51 as in Example 1. The potassium sulfate coated, plugged bags ¦ were then completely coated with a 0.65 mm thick membrane of 7¦ cellulose acetate in a small Wurster air suspension cGater. ?
81 (Air flow 15 m /min., air pressure 2 kg/cm 2 5 wt % acetone 9¦ solution of cellulose acetate, solution rate 50 ml/min., coat-~ol ing time 10 hr.) The bags were then oven dried at 60C for 11¦ 15 days and a hole was drilled in each membrane through to 12¦ plug bore. Flow moderators were made for each dispenser as 13¦ in Example 1.
14¦ The dispensers of Examples 1 and 2 were tested Ln ~51 vitro and in vivo by filling them with various fluids via I _ ~ _ 16¦ the plug bore, inserting the needle portion of the flow moder-17¦ ators through the plug bores down into the bags' interiors 18¦ and placing the dispensers in an appropriate environment.
19¦ In in vitro tests in water at 37C using FD ~ C Blue #l dye 201 in water as the fluid charge the dispensers dispensed the 21¦ solution at a flow rate of 1.7 x 10 3 ml/hr with ~ 1~3 x 10 4 22¦ ml/hr deviation. In in vivo tests using the same fluid charge 23¦ the dispensers were inserted subcutaneously into rats and pro-241 vided a flow rate of 1.0 x 10 ml/hr with ~ 8 x 10 ml/hr 25 ~ devlation.
,.: 271 .. ., . .
, . 281 . ' ' .
- 1,
23 Head 25 ls hemispher.ical and has a diameter approximately equal 24 to the outer diameter of dispenser 11. It also has a diamet-: 25 r.ical bore 26 for receiving tube 24. As seen .in Fig. 2, the ` 27 ` 32 ! ~c ~91 I
I ¦ flat side o head 25 fits against the top of plug 15 and the 2 ¦ top edge of bag 14. Thus the spherical surface of head 25 3 ¦ provides a smooth blunt surface that generally alLgns with 4 ¦ the exterior surface of the bag-solute layer~membrane assembly, S ¦ which bluntness and alignment are important if the d.ispenser 6 ¦ is to be used as an implant to adm.inister drugs to an.imals or 7 ¦ humans. Referring to Fig. 4, head 25 has three radial, equi-8 ¦ spaced grooves 27 in its spherical surface that intersect at 9¦ bore 26. The outer end of tube 24 is inset sl;ghtly from the 10¦ spherical surface of head 25 (Fig. 2) and thus grooves 27 11¦ serve as flow channels for composition 17 exiting from the 12¦ outer end of tube 24.
13¦ Fig. 3 illustrates an osmotic dispenser, generally 14¦ designated 28 that is identical to dispenser 11 except in one ¦ respect, namely outer membrane 12 encapsulates the top edge of .
16¦ bag 14 and the top of plug 15 as well as the arcuate surfaces 17 of layer 13 and band 22. As discussed below, this difference 18 is caused by a difference in the techniques by which the mem-brane 12 is applied to dispensers 11 and 28. Like dispenser 11, dispenser 2~ also consists of an outer, shape-reta.in.ing, semi-21 permeable membrane 12, an intermed:iate layer 13 of an osmoticall~ , 22 effective solute, an inner flexible bag 14 adapted to contain a 23 fluid 17, a plug 15, and a flow moderator 16. These components 24 are of identical structure, composition, and interelationship as their like numbered counterparts of dispenser 11 except for 26 the single difference mentioned above.
27 .
_9_ 3l ~2 : . : : ~ . :
~J~C ~91 1 Th~ components of di~p~nser 11 may be made and 2 assemble~l as follows. Bag 14 may be injection molded from 3 suitable polymer compositions by known techniques. Bag 14 4 is then pla~ed on a support means, such as a mandrel, and a suspension of the osmotically effective solute in an appro-6 priate suspending medium is prepared~ The supported bag 14 7 is then dipped repeatedly in the suspension to the desired 8 depth, with intervening drying periods, until a layer 13 of 9 desired thickness is formed. A solution of membrane material is then made and the supported, solute coated bag 1~ is dipped 11 repeatedly into the solution to a depth just above the top 12 edge of bag 14, with intervening drying periods, until a mem 13 brane 12 of desired thickness is formed. The mandrel is then 14 removed and plug 15, which may be injection molded by known techniques, is glued into the open end o~ bag 14~ Head 25 16 may be machined by known techniques if it is metal, or injec-17 tion molded by known techniques if made from a synthetic poly-18 mer. The end of tube 24 may be affixed within bore 26 by 19 press-fittingr gluing, or other known techniques.
Dispenser 28 may be assembled as ollows~ A solute 21 coated bag 14 is made as in the case of dispenser 11. Plu~
22 15 is then fixed in place in the open end of bag 14 as in the case of dispenser 11. Membrane 12 of dispenser 28 is 24 then applied to the solute coated, plugged bag 14 by air s~spension-solution coating techn;ques in a Wurster coating 2~
3() -10-I ~C~lgl ;i3~
1 ¦ apparatus. Such apparatus and techniques are ~ell known.
2 ¦ This manner of ormin~ mernbrane 12 encapsulates the entire 3 ¦ bag-solute layer-plug assembly. Accordingly, a hole must 4 ¦ be formed through membrane 12 to bore 23 of plug 15. This S ¦ may be done by drilling, punching, or equivalent techniques.
6 ¦ Dispensers 11 and 2~ may be filled with fluid 17 7 I via bore 23 of plug 15. For instance, the needle of a fluid B¦ loaded syringe may be inserted through bore 23 and the syr-9¦ inge's contents discharged into bag 14~ To insure that a 10¦ predetermined fluid pumping rate is ach;eved, it is desirable 11¦ to completely fill bag 14 with fluid 17. After the bag is ,21 filled, tube 24 of flow moderator 16 is inserted through bore 13¦ 23 to the position shown in Figs. 2 and 3. As described 14 above tube 24 functions as a capillary and inhibits loss of fluid 17 from the dispensers even though they are subjected 16 to substantial movement or tipped upside down.
17 Dispensers 11 and 28 operate in the following manner.
l8 Once placed in an aqueous environment, such as within a body 19 cavity or within body tissue, water from the environment i5 imbibed by layer 13 through membrane 12 at a rate determined 21 by the osmotic activity of the osmotically efEective solute, 22 and the osmotic reflection coefficient, composition, thickness, 23 and area of membrane 12. The imbibed water causes the volume 24 of the space between the inner surface of membrane 12 and the 26 exterior of bag 14 (the space initially occupied by layer 13) 29 -11~
: -l to increase. And since membrane 12 is shape-retaining, the 2 im~ibed water generates hydraulic pressure on the exterior of 3 bag 14 causing bag 14 to be squeezed inwardly. This squeezing 4 forces fluid 17 through tube 24 and out of the dispenser. Any air bubbles that were trapped within bag 14 dur~ing filling 6 will tend to be located adjacent to the inner end of plug 15 7 or the inner surface of baq 14, depending on the attitude of 8 the dispenser. Therefore, these air bubbles are not likely 9 to block the entrance to tube 24 and interrupt or impede the flow of fluid 17 therethrough.
l1 As indicated, fluid 17 may be an active agent com-12 position. In such instances the dispensers 11 or 28 will, of 13 course, discharge active agent directly. Alternatively, fluid 14 17 may be inert and the dispenser may be used simply as a IS displacement pump. In this alternative the dispenser will, 16 of course, have to be suitably interconnected to a reservoir 17 of the fluid (active agent) to be discharged, such that the 18 inert fluid displaces the fluid from the reservoir in a pre-l9 determlned regimen to the desired administration site. Such alternatives are particularly attractive in instances in which 22 ~ the fluid t e discharged is lncompatible with ba9 14.
2~ -12-:
I\RC 491 ~05~
EXAMPLES
2 ___ .
The following examples are intended to further illus-4 trate the above described dispensers and their manufacture.
These examples are not intended to limit the invention in any 6 way. Unless indicated otherwise, percentages and parts are 7 by weight.
9 Example l Cylindrical flexible bags (2.33 cm long, 3.81 mm 11 inner diameter, and 4.67 mm outer diameter) were injection molded at 180~C, 77-84 kg/cm 2 from an elastomeric styrene-131 butadiene copolymer (sold under the trade designation, Kraton 14¦ 2104). A mandrel was inserted into each bag and mandrel sup-~51 ported bags were attached to a dipping platform.
16¦ A suspension of potassium sulfate particles in 17¦ dioxane-cellulose acetate solution (50 wt %) was prepared 18¦ and the mandrel supported bags were dipped into the suspen-191 sion to a depth of 1.8 cm 4 times for 1 min. per dip with 201 an intervening 15 min. room air drying period. This dipping 21¦ coated the bags with an approx;mately 0.3 mm thick coating 221 of the suspension.
231 A solution of cellulose acetate (sold under the 241 trade designation, Eastman E-398~10) in acetone (15 wt %) 251 was prepared and the mandrel-supported, potassium sulfate ,' 261 `12!71 . . .
- 31 . .
32 .
.~ , ,.... , . . ' ' :, . , ,:. ., . :
~ AI~C 431~
~ S3~
1 I coatcd bags werc dipp~cl completely in the svlution 20 times 2 ¦ for 1 min. per dip with an intervening 15 min. drying period.
3 ¦ Following this dipping the bags were oven dried at 60C for 4 1 15 days. This dipping formed a cellulose acetate mernbrane S ¦ approximately 0.65 mm thick about the entire bag exterior, ¦ including the potassium sulfate coated portion thereof.
7 I Cylindrical plugs of the above described styrene~
B¦ butadiene copolymer were injection moldedO The plugs were -9¦ 0.5 cm long, had a 3.9 mm outer diameter, and had a central axial bore 0.76 mm in diarneter. The arcuate surfaces of the 11¦ plugs were coated with a glue bead of a 20 wt % cyclohexane 121 solution of the copolymer and the plugs were inserted into 13¦ the open ends of the potassium sulfate-cellulose acetate coated 14¦ bags. A 22 gauge needle was ;nserted through the bore of each ~sl plug and the plugged bags were placed in an oven at 60C for 16¦ 2 hr.
17¦ Flow moderators were prepared for each dispenser as 18¦ follows Head or cap members were injection molded from styrene-191 acrylonitrile copolymer. The heads were generally hemispherical 20¦ 6.6 mm in diameter with a 0.8 mm diameter dlametrical bore. The 21¦ arcuate surface of the heads had three equispaced grooves that 22¦ intersected the bore. Twenty-one gauge needles were cut in 15 m~
231 lengths, blunted, inserted into the heads and glued in place 2~1 therein with an epoxy resin.
': 2sl .
: 26 ::' 27 :, ' ~ A~C 491 I ~S33L~D~
1¦ Example 2 21 Inner bags were made and coated with potassium sulfate 31 as described in Example 1. Plugs Eor the potassium sulfate 41 coated bags were made and glued into the open ends of the bags 51 as in Example 1. The potassium sulfate coated, plugged bags ¦ were then completely coated with a 0.65 mm thick membrane of 7¦ cellulose acetate in a small Wurster air suspension cGater. ?
81 (Air flow 15 m /min., air pressure 2 kg/cm 2 5 wt % acetone 9¦ solution of cellulose acetate, solution rate 50 ml/min., coat-~ol ing time 10 hr.) The bags were then oven dried at 60C for 11¦ 15 days and a hole was drilled in each membrane through to 12¦ plug bore. Flow moderators were made for each dispenser as 13¦ in Example 1.
14¦ The dispensers of Examples 1 and 2 were tested Ln ~51 vitro and in vivo by filling them with various fluids via I _ ~ _ 16¦ the plug bore, inserting the needle portion of the flow moder-17¦ ators through the plug bores down into the bags' interiors 18¦ and placing the dispensers in an appropriate environment.
19¦ In in vitro tests in water at 37C using FD ~ C Blue #l dye 201 in water as the fluid charge the dispensers dispensed the 21¦ solution at a flow rate of 1.7 x 10 3 ml/hr with ~ 1~3 x 10 4 22¦ ml/hr deviation. In in vivo tests using the same fluid charge 23¦ the dispensers were inserted subcutaneously into rats and pro-241 vided a flow rate of 1.0 x 10 ml/hr with ~ 8 x 10 ml/hr 25 ~ devlation.
,.: 271 .. ., . .
, . 281 . ' ' .
- 1,
Claims (8)
1. An osmotically driven fluid dispenser compris-ing an elongated flexible inner bag closed at one end and open at the other end and adapted to contain the fluid, a fluid tight plug fitted into the open end of the bag, a port in the plug that provides a passageway from the interior of the bag to the exterior of the dispenser through which the fluid may be charged into the bag, an intermediate layer of an osmotically effective solute composition covering the exterior of the bag, and an outer shape-retaining semipermeable membrane covering the intermediate layer of osmotically effective solute composition, characterized in that: the osmotically effective solute composition only partly covers the exterior of the bag such that a band of the bag exterior proximate to the open end of the bag is not covered by the layer; the membrane forms a fluid tight seal with the exterior of the bag at said band;
and the dispenser includes a conduit that fits snugly through the port and extends into the interior of the bag after the fluid is charged to the bag to provide an outlet through which fluid may be dispensed from the bag under pressure.
and the dispenser includes a conduit that fits snugly through the port and extends into the interior of the bag after the fluid is charged to the bag to provide an outlet through which fluid may be dispensed from the bag under pressure.
2. The dispenser as claimed in claim 1 characterized in that the conduit extends into the bag interior over at least about 50% of the elongated dimension thereof.
3. The dispenser as claimed in claim 1 characterized in that the conduit extends into the bag interior over substantially the entire, but not all of, elongated dimension thereof.
4. The dispenser as claimed in claim 1 characterized in that the conduit is rigid.
5. The dispenser as claimed in claim 1 characterized in that the length and inner diameter of the conduit are such as to prevent substantial diffusive flow of fluid therethrough.
6. The dispenser as claimed in claim 1 characterized in that the exterior end of the conduit terminates in a blunt head.
7. The dispenser as claimed in claim 6 characterized in that said head is shaped to fit snugly against the exterior of the dispenser and form a substantially smooth continuous surface therewith.
8. The dispenser as claimed in claim 6 characterized in that the head has at least one groove in its exterior surface that communicates with the bore of the conduit to provide a flow channel for the fluid.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/618,492 US3987790A (en) | 1975-10-01 | 1975-10-01 | Osmotically driven fluid dispenser |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1053108A true CA1053108A (en) | 1979-04-24 |
Family
ID=24477937
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA261,892A Expired CA1053108A (en) | 1975-10-01 | 1976-09-23 | Osmotically driven fluid dispenser |
Country Status (12)
Country | Link |
---|---|
US (1) | US3987790A (en) |
JP (1) | JPS6039043B2 (en) |
AU (1) | AU499196B2 (en) |
CA (1) | CA1053108A (en) |
CH (1) | CH611800A5 (en) |
DE (1) | DE2644267A1 (en) |
DK (1) | DK156243C (en) |
FR (1) | FR2347059A1 (en) |
GB (1) | GB1517879A (en) |
IL (1) | IL50468A (en) |
IT (1) | IT1068729B (en) |
SE (1) | SE417158B (en) |
Families Citing this family (211)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4058122A (en) * | 1976-02-02 | 1977-11-15 | Alza Corporation | Osmotic system with laminated wall formed of different materials |
DE2626294C3 (en) * | 1976-06-11 | 1980-01-10 | Siemens Ag, 1000 Berlin Und 8000 Muenchen | Implantable dosing device |
DE2626348C3 (en) * | 1976-06-11 | 1980-01-31 | Siemens Ag, 1000 Berlin Und 8000 Muenchen | Implantable dosing device |
US4207890A (en) * | 1977-01-04 | 1980-06-17 | Mcneilab, Inc. | Drug-dispensing device and method |
US4203442A (en) * | 1977-08-29 | 1980-05-20 | Alza Corporation | Device for delivering drug to a fluid environment |
US4180073A (en) * | 1977-08-29 | 1979-12-25 | Alza Corporation | Device for delivering drug to biological environment |
US4223061A (en) * | 1977-10-25 | 1980-09-16 | Alza Corporation | Hydrophilic laminate useful for making dispensing device |
US4192308A (en) * | 1977-10-25 | 1980-03-11 | Alza Corporation | Device using prestretched polymer for dispensing medication |
US4304232A (en) * | 1979-03-14 | 1981-12-08 | Alza Corporation | Unit system having multiplicity of means for dispensing useful agent |
DE2911558A1 (en) * | 1979-03-23 | 1980-09-25 | Alza Corp | Liq. dispensing device - contains hydrophilic, water-insol. water-swellable polymer layer between compressible container and rigid casing |
FR2452918A1 (en) * | 1979-04-02 | 1980-10-31 | Alza Corp | Liq. dispensing device - contains hydrophilic, water-insol. water-swellable polymer layer between compressible container and rigid casing |
GB2048710B (en) * | 1979-05-07 | 1983-03-09 | Alza Corp | Osmotically driven fluid dispenser |
US4320758A (en) * | 1979-05-07 | 1982-03-23 | Alza Corporation | Osmotically driven fluid dispenser |
US4237893A (en) * | 1979-11-28 | 1980-12-09 | Alza Corporation | Cervical dilator |
US4299222A (en) * | 1980-01-08 | 1981-11-10 | Alza Corporation | Self-contained suction pump |
US4300558A (en) * | 1980-07-18 | 1981-11-17 | Alza Corporation | Self-driven fluid dispenser |
US4455144A (en) * | 1980-12-04 | 1984-06-19 | Alza Corporation | Dispenser constructed with semipermeable polymer-hydrophilic polymer wall |
US4340048A (en) * | 1981-03-28 | 1982-07-20 | Alza Corporation | Self-driven hypodermic injector |
FR2513243B1 (en) * | 1981-09-24 | 1983-11-18 | Commissariat Energie Atomique | |
US4474575A (en) * | 1982-02-01 | 1984-10-02 | Alza Corporation | Self-driven pump assembly and method of operation |
US4539004A (en) * | 1982-09-22 | 1985-09-03 | Alza Corporation | Self-driven pump assembly and method of operation |
AU591171B2 (en) * | 1983-11-02 | 1989-11-30 | Alza Corporation | Dispenser for delivering thermo-responsive composition |
US4595583A (en) * | 1984-03-19 | 1986-06-17 | Alza Corporation | Delivery system controlled administration of beneficial agent to ruminants |
US4663149A (en) * | 1984-03-21 | 1987-05-05 | Alza Corporation | Dispenser comprising inner and outer walls functioning as cooperative unit |
US4716031A (en) * | 1984-03-21 | 1987-12-29 | Alza Corporation | Drug dispenser comprising a multiplicity of members acting together for successfully dispensing drug |
US4692326A (en) * | 1984-03-21 | 1987-09-08 | Alza Corporation | Dispenser comprising inner positioned soft or hard capsule |
US4663148A (en) * | 1984-03-21 | 1987-05-05 | Alza Corporation | Dispenser comprising telescopically engaging members |
US4814180A (en) * | 1984-03-21 | 1989-03-21 | Alza Corporation | Agent dispenser comprising a semipermeable wall surrounding single-piece or two-piece container |
US4800056A (en) * | 1984-03-21 | 1989-01-24 | Alza Corporation | Process for making dispenser with cooperating elements |
US4765985A (en) * | 1985-03-05 | 1988-08-23 | Ciba-Geigy Corporation | Devices and methods for treating memory impairment |
US4680172A (en) * | 1985-03-05 | 1987-07-14 | Ciba-Geigy Corporation | Devices and methods for treating memory impairment |
US4865598A (en) * | 1985-08-16 | 1989-09-12 | Alza Corporation | Dispensing system for administering beneficial agent |
US4963141A (en) * | 1985-08-16 | 1990-10-16 | Alza Corporation | Dispensing system for administering beneficial agent formulation to ruminants |
US4865845A (en) * | 1986-03-21 | 1989-09-12 | Alza Corporation | Release rate adjustment of osmotic or diffusional delivery devices |
JP2598258B2 (en) * | 1987-01-30 | 1997-04-09 | セイコー電子工業株式会社 | Spatially resolved spectrometer |
US4772287A (en) * | 1987-08-20 | 1988-09-20 | Cedar Surgical, Inc. | Prosthetic disc and method of implanting |
US4929233A (en) * | 1988-08-26 | 1990-05-29 | Alza Corporation | Implantable fluid imbibing pump with improved closure |
US4946456A (en) * | 1988-08-26 | 1990-08-07 | Alza Corp. | Fluid imbibing pump activated by capillary action of a fabric or polymeric sleeve |
EP0374120A3 (en) * | 1988-12-13 | 1991-07-31 | Monsanto Company | Comosition for controlled release of polypeptides |
US5135523A (en) * | 1988-12-13 | 1992-08-04 | Alza Corporation | Delivery system for administering agent to ruminants and swine |
US5728088A (en) * | 1988-12-13 | 1998-03-17 | Alza Corporation | Osmotic system for delivery of fluid-sensitive somatotropins to bovine animals |
US4969884A (en) * | 1988-12-28 | 1990-11-13 | Alza Corporation | Osmotically driven syringe |
US4976966A (en) * | 1988-12-29 | 1990-12-11 | Alza Corporation | Delayed release osmotically driven fluid dispenser |
US4969872A (en) * | 1989-03-08 | 1990-11-13 | Alza Corporation | Intravenous system for delivering a beneficial agent with delivery rate control via permeable surface area variance |
US5030216A (en) * | 1989-12-15 | 1991-07-09 | Alza Corporation | Osmotically driven syringe |
US5024663A (en) * | 1990-02-21 | 1991-06-18 | Alza Corporation | Self-contained suction pump |
US5017381A (en) * | 1990-05-02 | 1991-05-21 | Alza Corporation | Multi-unit pulsatile delivery system |
US5151093A (en) * | 1990-10-29 | 1992-09-29 | Alza Corporation | Osmotically driven syringe with programmable agent delivery |
DE4301782C1 (en) * | 1993-01-23 | 1994-08-25 | Lohmann Therapie Syst Lts | Use of galanthamine to treat nicotine addiction |
DE4313928C2 (en) * | 1993-04-28 | 1996-09-19 | Lohmann Therapie Syst Lts | Transdermal therapeutic system for the controlled delivery of pilocarpine to the skin, process for its production and its use |
WO1995001203A2 (en) * | 1993-06-23 | 1995-01-12 | Cytotherapeutics, Inc. | Implantable membrane encapsulation apparatus |
DE4342173A1 (en) * | 1993-12-10 | 1995-06-14 | Lohmann Therapie Syst Lts | Pharmaceutical formulation for the prophylaxis or pretreatment of poisoning by organophosphorus cholinesterase inhibitors |
US5540665A (en) * | 1994-01-31 | 1996-07-30 | Alza Corporation | Gas driven dispensing device and gas generating engine therefor |
US5690952A (en) * | 1995-06-07 | 1997-11-25 | Judy A. Magruder et al. | Implantable system for delivery of fluid-sensitive agents to animals |
US6156331A (en) * | 1996-02-02 | 2000-12-05 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US6261584B1 (en) | 1996-02-02 | 2001-07-17 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US6395292B2 (en) * | 1996-02-02 | 2002-05-28 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
DE69734168T2 (en) * | 1996-02-02 | 2006-01-19 | Alza Corp., Mountain View | Implantable system with delayed release of active ingredient |
US6132420A (en) * | 1996-02-02 | 2000-10-17 | Alza Corporation | Osmotic delivery system and method for enhancing start-up and performance of osmotic delivery systems |
PT1066081E (en) | 1996-11-15 | 2003-12-31 | Alza Corp | OSMOTIC DISTRIBUTION SYSTEM AND PROCESS FOR IMPROVING THE START AND PERFORMANCE OF OSMOTIC DISTRIBUTION SYSTEMS |
ATE203157T1 (en) * | 1996-12-20 | 2001-08-15 | Alza Corp | INJECTABLE DEPOSIT GEL PREPARATION AND PRODUCTION METHOD |
ZA981610B (en) * | 1997-03-24 | 1999-08-26 | Alza Corp | Self adjustable exit port. |
US6994851B1 (en) | 1997-07-10 | 2006-02-07 | Mannkind Corporation | Method of inducing a CTL response |
US6977074B2 (en) * | 1997-07-10 | 2005-12-20 | Mannkind Corporation | Method of inducing a CTL response |
MY125849A (en) * | 1997-07-25 | 2006-08-30 | Alza Corp | Osmotic delivery system, osmotic delivery system semipermeable body assembly, and method for controlling delivery rate of beneficial agents from osmotic delivery systems |
CA2315890C (en) | 1997-12-22 | 2009-08-11 | Alza Corporation | Rate controlling membranes for controlled drug delivery devices |
US7890176B2 (en) * | 1998-07-06 | 2011-02-15 | Boston Scientific Neuromodulation Corporation | Methods and systems for treating chronic pelvic pain |
DE19906979B4 (en) | 1999-02-19 | 2004-07-08 | Lts Lohmann Therapie-Systeme Ag | Use of deoxypeganine for the treatment of nicotine addiction |
DE19906974C2 (en) * | 1999-02-19 | 2003-10-09 | Lohmann Therapie Syst Lts | Use of deoxypeganine for the treatment of alcoholism |
US6835194B2 (en) * | 1999-03-18 | 2004-12-28 | Durect Corporation | Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners |
US6541021B1 (en) * | 1999-03-18 | 2003-04-01 | Durect Corporation | Devices and methods for pain management |
WO2002043800A2 (en) * | 2000-11-29 | 2002-06-06 | Durect Corporation | Devices and methods for controlled delivery from a drug delivery device |
DE19923551A1 (en) * | 1999-05-21 | 2000-11-30 | Lohmann Therapie Syst Lts | Pharmaceutical preparation with the active ingredient diamorphine and its use in a method for treating opiate addiction |
US6471688B1 (en) | 2000-02-15 | 2002-10-29 | Microsolutions, Inc. | Osmotic pump drug delivery systems and methods |
US6616652B1 (en) | 2000-02-15 | 2003-09-09 | Microsolutions, Inc. | Osmotic pump delivery system with pre-hydrated membrane(s) and/or primable catheter |
US6582441B1 (en) | 2000-02-24 | 2003-06-24 | Advanced Bionics Corporation | Surgical insertion tool |
US7074803B2 (en) * | 2001-03-02 | 2006-07-11 | Durect Corporation | Opioid formulations |
US6569152B2 (en) | 2000-03-21 | 2003-05-27 | Farrington Pharmaceuticals, Llc | Sustained release delivery systems for solutes |
US20030211974A1 (en) * | 2000-03-21 | 2003-11-13 | Brodbeck Kevin J. | Gel composition and methods |
US6582418B1 (en) * | 2000-06-01 | 2003-06-24 | Medtronic, Inc. | Drug pump with reinforcing grooves |
US20050143789A1 (en) * | 2001-01-30 | 2005-06-30 | Whitehurst Todd K. | Methods and systems for stimulating a peripheral nerve to treat chronic pain |
US7493172B2 (en) * | 2001-01-30 | 2009-02-17 | Boston Scientific Neuromodulation Corp. | Methods and systems for stimulating a nerve originating in an upper cervical spine area to treat a medical condition |
US20060064140A1 (en) * | 2001-01-30 | 2006-03-23 | Whitehurst Todd K | Methods and systems for stimulating a trigeminal nerve to treat a psychiatric disorder |
EP1374855A1 (en) * | 2001-03-30 | 2004-01-02 | Takeda Chemical Industries, Ltd. | Medicinal solutions |
US6632217B2 (en) * | 2001-04-19 | 2003-10-14 | Microsolutions, Inc. | Implantable osmotic pump |
US7163688B2 (en) * | 2001-06-22 | 2007-01-16 | Alza Corporation | Osmotic implant with membrane and membrane retention means |
CN100446809C (en) * | 2001-11-14 | 2008-12-31 | 阿尔扎有限公司 | Injectable depot composition |
DE60239556D1 (en) | 2001-11-14 | 2011-05-05 | Durect Corp | CATHETERINJICIBLE DEPOT COMPOSITIONS AND THEIR USE |
US7853333B2 (en) | 2002-04-08 | 2010-12-14 | Ardian, Inc. | Methods and apparatus for multi-vessel renal neuromodulation |
US20070129761A1 (en) | 2002-04-08 | 2007-06-07 | Ardian, Inc. | Methods for treating heart arrhythmia |
US7653438B2 (en) | 2002-04-08 | 2010-01-26 | Ardian, Inc. | Methods and apparatus for renal neuromodulation |
US8131371B2 (en) | 2002-04-08 | 2012-03-06 | Ardian, Inc. | Methods and apparatus for monopolar renal neuromodulation |
US20080213331A1 (en) | 2002-04-08 | 2008-09-04 | Ardian, Inc. | Methods and devices for renal nerve blocking |
US8774913B2 (en) | 2002-04-08 | 2014-07-08 | Medtronic Ardian Luxembourg S.A.R.L. | Methods and apparatus for intravasculary-induced neuromodulation |
US8347891B2 (en) | 2002-04-08 | 2013-01-08 | Medtronic Ardian Luxembourg S.A.R.L. | Methods and apparatus for performing a non-continuous circumferential treatment of a body lumen |
US8145317B2 (en) | 2002-04-08 | 2012-03-27 | Ardian, Inc. | Methods for renal neuromodulation |
US20070135875A1 (en) | 2002-04-08 | 2007-06-14 | Ardian, Inc. | Methods and apparatus for thermally-induced renal neuromodulation |
US9308043B2 (en) | 2002-04-08 | 2016-04-12 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for monopolar renal neuromodulation |
US9636174B2 (en) | 2002-04-08 | 2017-05-02 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for therapeutic renal neuromodulation |
US8774922B2 (en) | 2002-04-08 | 2014-07-08 | Medtronic Ardian Luxembourg S.A.R.L. | Catheter apparatuses having expandable balloons for renal neuromodulation and associated systems and methods |
US7620451B2 (en) | 2005-12-29 | 2009-11-17 | Ardian, Inc. | Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach |
US7162303B2 (en) | 2002-04-08 | 2007-01-09 | Ardian, Inc. | Renal nerve stimulation method and apparatus for treatment of patients |
US7756583B2 (en) | 2002-04-08 | 2010-07-13 | Ardian, Inc. | Methods and apparatus for intravascularly-induced neuromodulation |
US6978174B2 (en) * | 2002-04-08 | 2005-12-20 | Ardian, Inc. | Methods and devices for renal nerve blocking |
US9308044B2 (en) | 2002-04-08 | 2016-04-12 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for therapeutic renal neuromodulation |
US8145316B2 (en) | 2002-04-08 | 2012-03-27 | Ardian, Inc. | Methods and apparatus for renal neuromodulation |
US20140018880A1 (en) | 2002-04-08 | 2014-01-16 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for monopolar renal neuromodulation |
US8150519B2 (en) | 2002-04-08 | 2012-04-03 | Ardian, Inc. | Methods and apparatus for bilateral renal neuromodulation |
US8175711B2 (en) | 2002-04-08 | 2012-05-08 | Ardian, Inc. | Methods for treating a condition or disease associated with cardio-renal function |
US7617005B2 (en) | 2002-04-08 | 2009-11-10 | Ardian, Inc. | Methods and apparatus for thermally-induced renal neuromodulation |
US7151961B1 (en) * | 2002-05-24 | 2006-12-19 | Advanced Bionics Corporation | Treatment of movement disorders by brain stimulation |
US20040001889A1 (en) | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
AR039729A1 (en) | 2002-06-25 | 2005-03-09 | Alza Corp | SHORT-TERM DEPOSIT FORMULATIONS |
DK1539101T3 (en) | 2002-07-31 | 2009-04-27 | Alza Corp | Injectable, multi-modal polymeric compositions and applications thereof |
CA2494342A1 (en) | 2002-07-31 | 2004-02-12 | Alza Corporation | Injectable depot compositions and uses thereof |
US7254449B2 (en) * | 2002-07-31 | 2007-08-07 | Advanced Bionics Corp | Systems and methods for providing power to one or more implantable devices |
CA2497867A1 (en) | 2002-09-06 | 2004-03-18 | Durect Corporation | Delivery of modulators of glutamate-mediated neurotransmission to the inner ear |
US20060009739A1 (en) * | 2002-09-06 | 2006-01-12 | Durect Corporation | Implantable flow regulator with failsafe mode and reserve drug supply |
ATE418323T1 (en) | 2002-11-06 | 2009-01-15 | Alza Corp | DEPOSIT DELAYED RELEASE FORMULATIONS |
US7014636B2 (en) * | 2002-11-21 | 2006-03-21 | Alza Corporation | Osmotic delivery device having a two-way valve and a dynamically self-adjusting flow channel |
US20040102476A1 (en) * | 2002-11-25 | 2004-05-27 | Chan Tai Wah | High concentration formulations of opioids and opioid derivatives |
US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
KR20060017749A (en) * | 2003-03-31 | 2006-02-27 | 알자 코포레이션 | Osmotic pump with means for dissipating internal pressure |
CN1767815A (en) * | 2003-03-31 | 2006-05-03 | 阿尔萨公司 | Non-aqueous single phase vehicles and formulations utilizing such vehicles |
BRPI0408921A (en) * | 2003-03-31 | 2006-03-28 | Alza Corp | osmotic distribution system and method for decreasing start times for osmotic distribution systems |
US20070083240A1 (en) * | 2003-05-08 | 2007-04-12 | Peterson David K L | Methods and systems for applying stimulation and sensing one or more indicators of cardiac activity with an implantable stimulator |
WO2005016241A2 (en) | 2003-05-16 | 2005-02-24 | Intermune, Inc. | Synthetic chemokine receptor ligands and methods of use thereof |
US20070184084A1 (en) * | 2003-05-30 | 2007-08-09 | Guohua Chen | Implantable elastomeric caprolactone depot compositions and uses thereof |
CA2527664A1 (en) * | 2003-05-30 | 2004-12-16 | Alza Corporation | Implantable elastomeric depot compositions, uses thereof and method of manufacturing |
WO2005040758A2 (en) * | 2003-10-24 | 2005-05-06 | Intermune, Inc. | Use of pirfenidone in therapeutic regimens |
US20050118246A1 (en) * | 2003-10-31 | 2005-06-02 | Wong Patrick S. | Dosage forms and layered deposition processes for fabricating dosage forms |
US7769461B2 (en) * | 2003-12-19 | 2010-08-03 | Boston Scientific Neuromodulation Corporation | Skull-mounted electrical stimulation system and method for treating patients |
US20080102119A1 (en) * | 2006-11-01 | 2008-05-01 | Medtronic, Inc. | Osmotic pump apparatus and associated methods |
US20050266087A1 (en) * | 2004-05-25 | 2005-12-01 | Gunjan Junnarkar | Formulations having increased stability during transition from hydrophobic vehicle to hydrophilic medium |
US20050267555A1 (en) * | 2004-05-28 | 2005-12-01 | Marnfeldt Goran N | Engagement tool for implantable medical devices |
US20080027513A1 (en) * | 2004-07-09 | 2008-01-31 | Advanced Bionics Corporation | Systems And Methods For Using A Butterfly Coil To Communicate With Or Transfer Power To An Implantable Medical Device |
EP3417895A1 (en) | 2004-07-28 | 2018-12-26 | Medtronic Ardian Luxembourg S.à.r.l. | Methods and devices for renal nerve blocking |
US8452407B2 (en) * | 2004-08-16 | 2013-05-28 | Boston Scientific Neuromodulation Corporation | Methods for treating gastrointestinal disorders |
US7937143B2 (en) | 2004-11-02 | 2011-05-03 | Ardian, Inc. | Methods and apparatus for inducing controlled renal neuromodulation |
US9358393B1 (en) | 2004-11-09 | 2016-06-07 | Andres M. Lozano | Stimulation methods and systems for treating an auditory dysfunction |
US7483746B2 (en) * | 2004-12-06 | 2009-01-27 | Boston Scientific Neuromodulation Corp. | Stimulation of the stomach in response to sensed parameters to treat obesity |
US20070038264A1 (en) * | 2004-12-21 | 2007-02-15 | Jaax Kristen N | Methods and systems for treating autism |
US20060161217A1 (en) * | 2004-12-21 | 2006-07-20 | Jaax Kristen N | Methods and systems for treating obesity |
US9327069B2 (en) | 2004-12-21 | 2016-05-03 | Boston Scientific Neuromodulation Corporation | Methods and systems for treating a medical condition by promoting neural remodeling within the brain |
US9095713B2 (en) * | 2004-12-21 | 2015-08-04 | Allison M. Foster | Methods and systems for treating autism by decreasing neural activity within the brain |
US9352145B2 (en) * | 2004-12-22 | 2016-05-31 | Boston Scientific Neuromodulation Corporation | Methods and systems for treating a psychotic disorder |
US8515541B1 (en) | 2004-12-22 | 2013-08-20 | Boston Scientific Neuromodulation Corporation | Methods and systems for treating post-stroke disorders |
EP2351577A1 (en) * | 2004-12-29 | 2011-08-03 | Mannkind Corporation | Methods to trigger, maintain and manipulate immune responses by targeted administration of biological response modifiers into lymphoid organs |
ATE401537T1 (en) * | 2005-01-06 | 2008-08-15 | Halton Oy | VENTILATION REGISTERS AND VENTILATION SYSTEMS |
US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
WO2006083761A2 (en) * | 2005-02-03 | 2006-08-10 | Alza Corporation | Solvent/polymer solutions as suspension vehicles |
US20060185665A1 (en) * | 2005-02-22 | 2006-08-24 | Bachinski Thomas J | Sauna fireplace |
US20060194724A1 (en) * | 2005-02-25 | 2006-08-31 | Whitehurst Todd K | Methods and systems for nerve regeneration |
US7853321B2 (en) * | 2005-03-14 | 2010-12-14 | Boston Scientific Neuromodulation Corporation | Stimulation of a stimulation site within the neck or head |
US8423155B1 (en) | 2005-03-14 | 2013-04-16 | Boston Scientific Neuromodulation Corporation | Methods and systems for facilitating stimulation of one or more stimulation sites |
US20060206165A1 (en) * | 2005-03-14 | 2006-09-14 | Jaax Kristen N | Occipital nerve stimulation to treat headaches and other conditions |
US7702385B2 (en) * | 2005-11-16 | 2010-04-20 | Boston Scientific Neuromodulation Corporation | Electrode contact configurations for an implantable stimulator |
US7848803B1 (en) | 2005-03-14 | 2010-12-07 | Boston Scientific Neuromodulation Corporation | Methods and systems for facilitating stimulation of one or more stimulation sites |
US7959938B2 (en) * | 2005-03-15 | 2011-06-14 | Intarcia Therapeutics, Inc. | Polyoxaester suspending vehicles for use with implantable delivery systems |
GB2442396B (en) * | 2005-07-22 | 2011-05-11 | Univ Utah Res Found | Osmotically driven dispense pump and related components for use in high pressure applications |
US20070027105A1 (en) * | 2005-07-26 | 2007-02-01 | Alza Corporation | Peroxide removal from drug delivery vehicle |
US7684858B2 (en) * | 2005-09-21 | 2010-03-23 | Boston Scientific Neuromodulation Corporation | Methods and systems for placing an implanted stimulator for stimulating tissue |
EP1948246B1 (en) | 2005-11-14 | 2017-05-03 | Theragene Pharmaceuticals, Inc. | Stem cell factor therapy for tissue injury |
US7729758B2 (en) | 2005-11-30 | 2010-06-01 | Boston Scientific Neuromodulation Corporation | Magnetically coupled microstimulators |
US7610100B2 (en) * | 2005-12-30 | 2009-10-27 | Boston Scientific Neuromodulation Corporation | Methods and systems for treating osteoarthritis |
US7835803B1 (en) * | 2006-01-17 | 2010-11-16 | Boston Scientific Neuromodulation Corporation | Lead assemblies with one or more switching networks |
US8175710B2 (en) * | 2006-03-14 | 2012-05-08 | Boston Scientific Neuromodulation Corporation | Stimulator system with electrode array and the method of making the same |
US7777641B2 (en) * | 2006-03-29 | 2010-08-17 | Advanced Bionics, Llc | Systems and methods of facilitating communication between a first and second device |
MX2008014870A (en) | 2006-05-30 | 2009-02-12 | Intarcia Therapeutics Inc | Two-piece, internal-channel osmotic delivery system flow modulator. |
US8504163B1 (en) | 2006-06-30 | 2013-08-06 | Boston Scientific Neuromodulation Corporation | Cranially mounted stimulation systems and methods |
US8401654B1 (en) | 2006-06-30 | 2013-03-19 | Boston Scientific Neuromodulation Corporation | Methods and systems for treating one or more effects of deafferentation |
ES2422864T3 (en) | 2006-08-09 | 2013-09-16 | Intarcia Therapeutics, Inc | Osmotic release systems and piston units |
US7445528B1 (en) | 2006-09-29 | 2008-11-04 | Boston Scientific Neuromodulation Corporation | Connector assemblies |
US7347746B1 (en) | 2006-10-27 | 2008-03-25 | Boston Scientific Neuromodulation Corporation | Receptacle connector assembly |
WO2008133908A2 (en) | 2007-04-23 | 2008-11-06 | Intarcia Therapeutics, Inc. | Suspension formulations of insulinotropic peptides and uses thereof |
EP2240155B1 (en) | 2008-02-13 | 2012-06-06 | Intarcia Therapeutics, Inc | Devices, formulations, and methods for delivery of multiple beneficial agents |
EP3025727A1 (en) | 2008-10-02 | 2016-06-01 | The J. David Gladstone Institutes | Methods of treating liver disease |
US8652129B2 (en) | 2008-12-31 | 2014-02-18 | Medtronic Ardian Luxembourg S.A.R.L. | Apparatus, systems, and methods for achieving intravascular, thermally-induced renal neuromodulation |
JP2012520884A (en) | 2009-03-18 | 2012-09-10 | ザ ボード オブ トラスティーズ オブ ザ リランド スタンフォード ジュニア ユニバーシティー | Methods and compositions for treating flaviviridae viral infections |
WO2011037623A1 (en) | 2009-09-28 | 2011-03-31 | Intarcia Therapeutics, Inc. | Rapid establishment and/or termination of substantial steady-state drug delivery |
FR2954936B1 (en) * | 2010-01-06 | 2012-03-02 | Oreal | DEVICE FOR CONDITIONING AND APPLICATION COMPRISING AN APPLICATION MEMBER. |
US9215921B2 (en) | 2010-01-06 | 2015-12-22 | L'oreal | Packaging and applicator device including an applicator member |
CN107007348B (en) | 2010-10-25 | 2019-05-31 | 美敦力Af卢森堡有限责任公司 | For the estimation of nerve modulation treatment and device, the system and method for feedback |
US20120208755A1 (en) | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
WO2012175698A1 (en) | 2011-06-23 | 2012-12-27 | Université Libre de Bruxelles | Therapeutic use of all-trans retinoic acid (atra) in patients suffering from alcoholic liver disease |
EP2751291B1 (en) | 2011-09-01 | 2018-08-15 | University of Southern California | Methods for preparing high throughput peptidomimetics, orally bioavailable drugs and compositions containing same |
CN104066432B (en) | 2011-12-06 | 2017-06-13 | 小利兰·斯坦福大学董事会 | Method and composition for treating viral disease |
AU2013230781B2 (en) | 2012-03-08 | 2015-12-03 | Medtronic Af Luxembourg S.A.R.L. | Ovarian neuromodulation and associated systems and methods |
RU2644933C2 (en) | 2012-03-08 | 2018-02-14 | Медтроник Аф Люксембург Сарл | Biomarker samples selection as part of devices for neuromodulation and relevant systems and methods |
US20140110296A1 (en) | 2012-10-19 | 2014-04-24 | Medtronic Ardian Luxembourg S.A.R.L. | Packaging for Catheter Treatment Devices and Associated Devices, Systems, and Methods |
CN105764491A (en) | 2013-12-09 | 2016-07-13 | 度瑞公司 | Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same |
US9980766B1 (en) | 2014-03-28 | 2018-05-29 | Medtronic Ardian Luxembourg S.A.R.L. | Methods and systems for renal neuromodulation |
US10194980B1 (en) | 2014-03-28 | 2019-02-05 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for catheter-based renal neuromodulation |
US10194979B1 (en) | 2014-03-28 | 2019-02-05 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for catheter-based renal neuromodulation |
US9889085B1 (en) | 2014-09-30 | 2018-02-13 | Intarcia Therapeutics, Inc. | Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c |
CN113598842A (en) | 2015-06-03 | 2021-11-05 | 因塔西亚制药公司 | Implant placement and removal system |
WO2017023863A1 (en) | 2015-07-31 | 2017-02-09 | Research Institute At Nationwide Children's Hospital | Peptides and antibodies for the removal of biofilms |
EP3365027B1 (en) | 2015-10-14 | 2022-03-30 | Research Institute at Nationwide Children's Hospital | Hu specific antibodies and their use in inhibiting biofilm |
WO2017168174A1 (en) | 2016-04-02 | 2017-10-05 | N4 Pharma Uk Limited | New pharmaceutical forms of sildenafil |
EP3458084B1 (en) | 2016-05-16 | 2020-04-01 | Intarcia Therapeutics, Inc | Glucagon-receptor selective polypeptides and methods of use thereof |
USD840030S1 (en) | 2016-06-02 | 2019-02-05 | Intarcia Therapeutics, Inc. | Implant placement guide |
USD860451S1 (en) | 2016-06-02 | 2019-09-17 | Intarcia Therapeutics, Inc. | Implant removal tool |
WO2018002673A1 (en) | 2016-07-01 | 2018-01-04 | N4 Pharma Uk Limited | Novel formulations of angiotensin ii receptor antagonists |
WO2018115888A1 (en) | 2016-12-21 | 2018-06-28 | N4 Pharma Uk Limited | Novel formulations of aprepitant |
EP3565580B1 (en) | 2017-01-03 | 2024-03-06 | i2o Therapeutics, Inc. | Continuous administration of exenatide and co-adminstration of acetaminophen, ethinylestradiol or levonorgestrel |
EP3565589A1 (en) | 2017-01-04 | 2019-11-13 | Research Institute at Nationwide Children's Hospital | Dnabii vaccines and antibodies with enhanced activity |
JP2020506221A (en) | 2017-01-04 | 2020-02-27 | リサーチ インスティチュート アット ネイションワイド チルドレンズ ホスピタル | Antibody fragments for the treatment of biofilm-related disorders |
USD933219S1 (en) | 2018-07-13 | 2021-10-12 | Intarcia Therapeutics, Inc. | Implant removal tool and assembly |
CN110353973B (en) * | 2019-07-03 | 2021-06-08 | 合肥职业技术学院 | Medicine package composition release in hot spring water body |
US20220275064A1 (en) | 2019-07-08 | 2022-09-01 | Research Institute At Nationwide Children's Hospital | Antibody compositions for disrupting biofilms |
CN115666621A (en) | 2020-01-13 | 2023-01-31 | 度勒科特公司 | Sustained release drug delivery systems with reduced impurities and related methods |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3604417A (en) * | 1970-03-31 | 1971-09-14 | Wayne Henry Linkenheimer | Osmotic fluid reservoir for osmotically activated long-term continuous injector device |
US3760804A (en) * | 1971-01-13 | 1973-09-25 | Alza Corp | Improved osmotic dispenser employing magnesium sulphate and magnesium chloride |
SE398976B (en) * | 1971-01-13 | 1978-01-30 | Alza Corp | OSMOTIC DOSAGE DEVICE |
CA949513A (en) * | 1971-01-13 | 1974-06-18 | Alza Corporation | Osmotic dispenser |
US3760984A (en) * | 1971-09-29 | 1973-09-25 | Alza Corp | Osmotically powered agent dispensing device with filling means |
US3845770A (en) * | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3929132A (en) * | 1973-04-10 | 1975-12-30 | Alza Corp | Osmotic dispenser |
-
1975
- 1975-10-01 US US05/618,492 patent/US3987790A/en not_active Expired - Lifetime
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1976
- 1976-09-06 AU AU17488/76A patent/AU499196B2/en not_active Expired
- 1976-09-10 IL IL50468A patent/IL50468A/en unknown
- 1976-09-20 GB GB38897/76A patent/GB1517879A/en not_active Expired
- 1976-09-22 DK DK426776A patent/DK156243C/en not_active IP Right Cessation
- 1976-09-23 CA CA261,892A patent/CA1053108A/en not_active Expired
- 1976-09-28 JP JP51116468A patent/JPS6039043B2/en not_active Expired
- 1976-09-30 DE DE19762644267 patent/DE2644267A1/en active Granted
- 1976-09-30 CH CH1237976A patent/CH611800A5/xx not_active IP Right Cessation
- 1976-09-30 SE SE7610833A patent/SE417158B/en not_active IP Right Cessation
- 1976-09-30 IT IT69346/76A patent/IT1068729B/en active
- 1976-10-01 FR FR7629595A patent/FR2347059A1/en active Granted
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DK156243B (en) | 1989-07-17 |
IL50468A0 (en) | 1976-11-30 |
FR2347059A1 (en) | 1977-11-04 |
JPS6039043B2 (en) | 1985-09-04 |
US3987790A (en) | 1976-10-26 |
DK156243C (en) | 1989-12-04 |
JPS5244227A (en) | 1977-04-07 |
DE2644267C2 (en) | 1989-01-05 |
SE7610833L (en) | 1977-04-02 |
GB1517879A (en) | 1978-07-12 |
AU499196B2 (en) | 1979-04-05 |
DK426776A (en) | 1977-04-02 |
FR2347059B1 (en) | 1979-09-28 |
DE2644267A1 (en) | 1977-04-14 |
CH611800A5 (en) | 1979-06-29 |
IT1068729B (en) | 1985-03-21 |
AU1748876A (en) | 1978-03-16 |
IL50468A (en) | 1978-12-17 |
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