CA1092469A - Osmotically driven active agent dispenser and process for making same - Google Patents
Osmotically driven active agent dispenser and process for making sameInfo
- Publication number
- CA1092469A CA1092469A CA291,085A CA291085A CA1092469A CA 1092469 A CA1092469 A CA 1092469A CA 291085 A CA291085 A CA 291085A CA 1092469 A CA1092469 A CA 1092469A
- Authority
- CA
- Canada
- Prior art keywords
- active agent
- dispenser
- compartment
- housing
- drug
- 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
-
- 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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
Abstract
TITLE: OSMOTICALLY DRIVEN ACTIVE AGENT DISPENSER
AND PROCESS FOR MAKING SAME
ABSTRACT OF THE DISCLOSURE
An osmotically driven dispenser for releasing active agents, such as drugs, to liquid-containing environments, such as various body sites. The dispenser comprises a housing made from a semipermeable material, a flexible partition that divides the housing interior into two compartments, an initially nonflowable, osmotically effective active agent composition filling one of the compartments, an osmotically effective com-position filling the other compartment, and an outlet passageway extending through the housing to the active agent-containing compartment. In operation liquid is imbibed from the environ-ment through the housing into both compartments, thereby con-verting the active agent composition to a flowable form and causing the flexible partition to displace into the active agent-containing compartment and force active agent therefrom via the outlet passageway. The release rate of active agent from the dispenser is a function of the combined rate of liquid influx into both compartments.
AND PROCESS FOR MAKING SAME
ABSTRACT OF THE DISCLOSURE
An osmotically driven dispenser for releasing active agents, such as drugs, to liquid-containing environments, such as various body sites. The dispenser comprises a housing made from a semipermeable material, a flexible partition that divides the housing interior into two compartments, an initially nonflowable, osmotically effective active agent composition filling one of the compartments, an osmotically effective com-position filling the other compartment, and an outlet passageway extending through the housing to the active agent-containing compartment. In operation liquid is imbibed from the environ-ment through the housing into both compartments, thereby con-verting the active agent composition to a flowable form and causing the flexible partition to displace into the active agent-containing compartment and force active agent therefrom via the outlet passageway. The release rate of active agent from the dispenser is a function of the combined rate of liquid influx into both compartments.
Description
- ~092469 United States 3,760,805 issued September 25, 1973 to ALza Corp.
describes an osmotically driven drug dispenser that consists of a rigid housing~ a flexible partition that divides the housing interior into two compartments, a flowable drug composition filling one of the compartments, an osmotically effective solute within the other compartment, and an outlet passageway through the housing into the drug-conta;n;ng compartment. The portion of the housing that defines the osmotically effective solute-con-taining compartment is semipermeable; whereas the portion that defines the drug-containing compartment is impermeable. When placed in a water-contain-ing enviroDment, water is imbibed through the semipermeable portion of the housing into the solute-containing compartment causing that compartment to increase in volume by stretching the flexible partition and displacing it into the drug-containing ~on~rtment. Such displacement forces the flowable drug composition from the dispenser via the outlet.
United States 3,916,899 issued November 4,1975 to ALza Corp.
describes an osmotically driven drug dispenser that consists of a rigid, semipermeable housing whose interior is filled with an osmotically effect-ive drug compositionO The housing has a specifically sized out-~et passage-way through it. When the dispenser is placed in a water-containing environ-ment, water permeates through the semipermeable housing and dissolves thedrug composition. The osmotic imbalance between the resulting solution and the liquid in the environment causes water to be imbibed into the housing interior thus creating pressure therein which forces the drug solution into the enviroDment ~ia the outlet passageway.
~09Z469 The invention is an osmotically driven dispenser for use in a liquid-containing environment aomprising: a substantially rigid housing, a movable partition within the housing that divides the housing interior into a first c~rpartment and a seoond comparbncnt, with the portion of the housing that defines the first cYmpartment having an outlet passageway and the portion of the housing that defines the seaond ccnpartment being semi-permeable; active agent aomposition aontained within and filling the first compmrtment; and an osmotically effective aomposition in the second coopartment that imbibes liquid from the environment thnough the housing into the seaond comparbment causi~g pressure to be exerted on the movable partitian and active agent aomposition to be displaced from the first aom~
partment in response to that pressure through the outlet into the enviranment, characterized in that the portian of the housing that defines the first ccmpartment is semipermeable and the active ag nt composition is in a nonflcwable form ;n;tially and is osmotically effective such that liquid is imbibed fram the environment into the first coLparbment to aonvert the active agent aompositian into a flowable farm and the mass rate at which active agent aomposition is dispensed is a functian of the oombined vol~me rates of liquid imbibitian into the first and seaond a mpartJents.
The inventian also includes a process far making the above described dispenser characterized by forming one of either the active agent aomposLtion or the osmotically effec-tive aomposition into a body of predetermined shape, aoating a 1092~69 surface of said body with a flexible material to form the partition, forming the other of said compositions into a body of predetermined shape, attaching the bodies at said surface, coating the attached bodies,with a semipermeable material to form the housing, and forming the outlet passageway in the housing.
-The drawings illustrate several embodiments of theinvention and depict graphically their performance. In the - drawings:
Figure lA is an isometric view of a dispenser accord-ing to the invention designed for orally administering drugs;
Figures lB - lF are sectional views of the dispen~ser of Figure lA illustrating the dispenser at various stages in its operation;
: : .
Figure 2 is a sectional view of another embodiment of the invention designed for the same use as the dispenser of ~ Fig. lA;
: ~ .
Figure 3 is a sectional view of yet another embodiment of the invention designed for the same use as the dispenser of Fig. lA;
Figure 4 is a side elevational view, partly in section, of an embodiment of the invention that is designed for releas-ing dEug in the vaginal cavity;
"- 109Z469 Figure 5 is a front view of a human eye with an ocular embodiment of the invention in operative position in the eye;
Figure 6 is a graph showing the actual and theoretical release rates of the dispensers of Example 1.
Figure 7 is a graph showing the actual and theoretical release rates of the dispensers of Example 2.
Figures 8A and 8B are graphs illustrating the perform-ance of the dispensers of Example 3.
Figures 9A and 9B are graphs illustrating the perform-ance of the dispensers of Example 4; and Figure 10 is a graph showing the actual and theoretical release rates of the dispensers of Example 5.
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- In the drawings and specification, like parts in related - figures are identified by like numbers.
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. In Figures lA through lF, the dispenser is generally designated 10. Dispenser 10 consists of a housing 11 formed by a semipermeable wall 12 that partly defines the perimeters of a first compartment 13 and a second compartment 14. Housing 11 has an ouelet passageway 15 in it that extends from compartment _5_ ~
... ., ~
~., . . " . . -` `" lO9Z469 13 to the exterior of dispenser 10. The remainders of the perimeters of compartme~ts 13 and 15 are defined by a flexible membrane 18. ~embrane 18 separates the compartments and forms a common wall or partition therebetween. Compartment 13 is filled with an initially nonflowable drug composition 16 that in solution exhibits an osmotic pressure gradient across wall 12 against the gastrointestinal fluids (that is, the osmotic pressure of drug composition 16 in solution is greater than the osmotic pressure of the gastrointestinal fluids. Sucn compositions that exhibit greater osmotic pressure than the environment liquid are said to be "osmotically effective~.) The osmotic effectiveness of drug composition 16 may be attributable to the drug itself and/or to one or more added osmotically effective compounds (hereinafter called Uosma-gents~). Compartment 14 is filled with one or more osmagents 17. ~embrane 18 is free of passageways and is formed of a flexible material that can stretch or distend from an initial unstretched position (Figure lB) through partly stretched positions (Figures lC through lE) to a fully stretched position (Figure lF).
Dispenser 10 operates in the following manner. Once it is swallowed, water 19 from the gastrointestinal fluid permeates through wall 12 into compartments 13 and 14 to dissolve the soluble components of drug composition 16 and osmagent 17, respectively, therein. The dissolving of drug composition 16 forms a flowable solution or slurry thereof.
Further water is imbibed into each compartment due to the lO9Z~69 osmotic pressure gradients between ~he gastrointestinal fluid and the respective solutions of drug composition 16 and osmagent 17. The rates at which water is so imbibed into the compart-ments will depend upon the water permeability of wall 12 and the magnitudes of said gradients. The water imbibed into compa~tment 14 exerts pressure on flexible membrane 18 causing it to stretch and displace into compartment 13, thereby forcing the solution or slurry of drug composition out of compartment 13 via passageway 15. The displacement of membrane 18 into compartment 13 continuously diminishes the volume of compartment 13 as shown in Figs. lC - lF. This continuous diminishment of volume keeps the solution of drug composition at saturation concentration, which, in turn, keeps the osmotic pressure gradient between the solution and the gastrointestinal fluid constant. This is especially important in instances in which the drug involved is highly soluble in water. The continuous imbibition of water into compartment 13 contributes to forcing the solution or slur`ry of drug composition 16 therefrom.
Accordingly, drug composition 16 is transformed within compart-ment 13 from a solid or other nonflowable form, e.g. gel, paste, or semisolid, into a flowable solution or slurry and is pumped from compartment 13 in response to the displacement of membrane 18 and the influx of water into compartment 13 through semipermeable wall 12. The combined force exerted by the displacement of membrane 18 and the influx of water into compartment 13 facilitates the dispensing of slurries from compartment 13, such as are formed when the drug is highly water insoluble.
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. ARC 551 lO9Z469 Figures 2 and 3 depict other embodiments of the invention that are similar to dispenser 10 of Figures lA - lF in structure and operation, except as regards the configurations of the housing and of the membrane that divides the housing interior into the drug composition and osmagent compartments. Figure 2 illustrates an ellipsoidally-shaped dispenser 10 in which a greater portion of the perimeter of drug composition compartment 13 is defined by mem~rane 18. Figure 3 depicts a substantially parallelipiped-shaped dispenser 10 in which an even greater portion of the perimeter of the drug composition compartment 13 is defined by membrane 18.
Figure 4 shows a vaginal dispenser 10 designated for placement in a vagina. Dispenser 10 has an elongated, cylin-drical, self-sustaining shape with a rounded lead end 20 and a trailing end 21. It is equipped with a cord 22 for easily removing it from a vagina. Vaginal dispenser 10 is structur-ally and operationally similar to the dispensers of Figures 1 -3. Membrane 18 is shown at various stages of displacement (designated 18a - 18c) in Figure 4.
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Figure 5 shows an ocular dispenser 10 in operative position in an eye 25. Ocular dispenser 10, except for its size and shape, is structurally and functionally identical to dispenser 10 of Figs. lA - lF. Eye 25 includes an upper eyelid 26 with eyelashes 27, a lower eyelid 28 witn eyelashes 29, and an eyeball 30 covered for the greater part by sclera 31 and at its center area by cornea 32. Eyel-ids 26 and 28 are lined with palpebral conjunctiva, and sclera 31 is lined with a bulbar conjunctiva that covers the exposed surface of eyeball 30. The portion of the palpebral conjunctiva which linès upper eyelid 1092~6~
26 and the underlying portion of the bulbar con~unctiva defines an upper cul-de-sac, while that portion of the palpebral con-junctiva which lines lower eyelid 28 and the underlying portion of the bulbar conjunctiva defines a lower cul-de-sac. Ocular dispenser 10 is designed for placement in the upper or lower cul-de-sac and its drug compartment contains an ophthalmic drug for release to eye 25 at a controlled and continuous rate over a prolonged period of time.
As illustrated by Figures 1 - 5, the invention can take a wide variety of shapes, sizes and forms for delivering drug to different body sites. The invention also can be sized, shaped and adapted for delivering appropriate active agents to streams, aquariums, fields, chemical reactions, anâ other liquid-containing environments of use.
In drug dispensing embodiments of the invention, wall 12 should be made from a material that is biologically compat-ible with the body site at which the dispenser is to be placed, permeable to water, and impermeable to the drug composition and osmagent, The material may be nonerodible or erodible but must maintain its rigid integral structure during the dispens-ing lifetime of the dispenser. Such materials include cellulose acetate, cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, cellulose diacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, poly-urethane, sulfonated polystyrenes, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbamate, cellulose acetate chloroacetate, cellulose dipalmitate, _g_ cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate, cellulose acetate valerate, cellulose acetate succinate~ cellulose propionate succinate, methyl cellulose, cellulose acetate p-toluene sulfonate, and cellulose acetate butyrate. Generally, these materials will have a water permeability of 10 5 to 10 1 cc mil/cm2 hr atm expres-sed per atmosphere by hydrostatic pressure difference across wall 12 at the temperature of use. Wall 12 will usually be about 150 to 450 microns thick, preferably 2~0-300 microns thick.
Membrane 18 may be formed ~rom the same materials as wall lo 12 or from known flexible polymers. When membrane 18 is made from lG the same material as wall 12 it may be made flexibl~ by (1) control-ling its thickness to about 50 to 200 microns~ and (2) by optionaIly adding from 0.01% to 40% of a suitable plasticizerO In such instances there may be water passage through membrane 18 from one of the com-partments 13, 14 to the other depending upon the particular drug com-position and osmagnet that are employed.
Passageway 15 should have the same dimensions as the pas-sageways of the dispensers described in United States 3,916,899 issued November 4, 1975 to ALza Corp~ Procedures for forming such passageways are described in United States 3,916,899 issued Novem-ber 4, 1975 to ALza Corp. and United States 4,016,880 issued April 12, 1977.
As indicated above~ compounds that may be used as osmagnets in the invention must exhibit an osmotic pressure in solution that is signi~ica~ ygreater than that of the ~` lO9Z~69 environment liquid. Thus, in drug dispensing embodiments the osmotic pressure of the solution of osmagent will be in excess of about 750 kPa. Osmagents useful in such embodiments include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, calcium carbonate, sodium sulfate, calcium sulfate, potassium acid phosphate, calcium lactate, d-mannitol, urea, inositol, magnesium succinate, tar-taric acid, starches, and carbohydrates such as raffinose, succrose, glycose, and mixtures thereof.
- The term "active agent" as used herein includes any compound, composition of motter or mixture thereof that can be delivered from tne dispenser to produ.ce a beneficial and useful result. Active agents include pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, a~ti-oxidants, plant growth promoters, plant growth inhi~itors, preservatives, anti-preservatives, dis-infectants, sterilization agents, catalysts, chemical reactants, fermentation agents, foods, food supplements, nutrients, cos-metics, drugs, vitamins, sex sterilants, fertility inhibitors, fertility promoters, air purifiers, micro-organism attenuators, and other agents that benefit the environment of use. The term ~drug~ as used herein includes any physiologically or pharma-cologically active substance that produces a localized or systemic effect in animals, including humans.
`` ~09Z~69 The invention dispensers may be manufactured by the following techniques. Active agent composition 16 is formed into a solid, semi-solid or pressed state by conventional methods such as ballmilling, calendering, stirring or roll-milling followed by pressing or tableting into a body of preselected shape. A semipermeable wall is then formed about the body of active agent composition by molding, spraying, or dipping. Alternatively the wall can be cast or otherwise formed and then filled with composition 16 and closed. A
portion of this wall constitutes membrane 18. Osmagent 17 is then pressed or formed into a body of preselected shape and is attached by adhesives or other joining techniques to the walled active agent composition. Finally, the resulting assembly is then surrounded by molding, spraying, or dipping with semipermeable wall 12. Passageway 15 may be formed in the portion of the wall about the active agent composition by the methods described in U.S. 3,916,-899. Of course, the above technique may be carried out by first forming a walled osmagent body, attaching a body of an active agent composition thereto, surrounding the resulting assembly with a semiperme-able material, and forming passageway I5. Alternatively both bodies can be surrounded by a semipermeable wall and the two walled bodies joined together by an adhesive.
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Another manufacturing process involves charging layers of the active agent composition, flexible material, and osmagent into the die of a tabletting machine, compressing the three layers into a composite tablet, coating the composite tablet with a semipermeable material, and forming the outlet passage-way in the coating.
`" 109Z~69 The following examples illustrate further embodiments of the invention and are not intended to limit the invention in any manner. Unless otherwise indicated, percentages are by weight.
EXA~PLE 1 A dispenser for delivering the antiarrhythmic and antifibrillatory drug procainamide hydrochloride to the gastro-intestinal tract was manufactured as follows: 225 mg of pro-cainamide hydrochloride was pressed into a solid mass in a commercially available Manesty tableting machine to a Stoke's hardness of 8 kg. Next, the mass was coated in a standard air suspension machine with a film formed from a 5% solution of cellulose acetate having an acetyl content of 32~. The solution was made by dissolving 155 g cellulose acetate in a mixed sol-vent system of 3300 ml acetone and 330 ml water. The freshly formed film had a thickness of 125 microns.
Next, 350 mg of sodium chloride was pressed in the ~anesty machine to a Stoke's hardness of 8 kg. The pressed sodium chloride had a shape identical to the shape of the pressed procainamide hydrochloride. Then, a small drop of liquid cellulose acetate was spread onto one surface of the pressed sodium chloride and this surface was placed against a corresponding surface of the film-coated procainamide hydro-chloride. The two united masses were then coated in the air suspension machine with cellulose acetate per the above method to a wall thickness of 250 microns. Finally, an osmotic passageway having a diameter of 250 microns was drilled through the coating facing the procainamide hydrochloride using a CO2 la`ser.
. ''' ~' . ARC 551 `` 109Z~69 The release rate of procainamide hydrochloride was mea-sured according to known procedures by placing them in water with agitation and periodically determining the concentration of the drug in the water by spectrophotometric analysis.
Release rates were calculated from these measurements. Fig.
6 plots the release rate versus time, with actual release shown by a solid line and theoretical release by a dashed line.
Dispensers were made as in Example 1, except that the membrane separating the procainamide hydrochloride and the sodium chloride had a thickness of 190 microns and the wall had a thickness of 190 microns. The release rate of these dispensers was determined by the procedure described in Example 1. me resùlts are shown in Figure 7, with actual release rate designated by a solid line and theoretical release rate designated by a dashed line.
The general procedure of Example 1 was used, with the variations indicated below, to make other dispensers for admin-istering procainamide hydrochloride orally. The procainamide hydrochloride body was coated with a 75 micron thick film formed ` from a 5% solution of 70% cellulose acetate having an acetyl content of 38.3%, and 30% polyethylene glycol having a molec-ular weight of 400 dissolved in a 80:20 by weight methylene chloride-methanol solvent system, and then bonaed to a pressed 109~46~
body of ammonium chloride. The two bodies were finally coated with the cellulose acetate solution of Example 1 to form an exterior wall having a thickness of 90 microns. The outlet passageway was 200 microns in diameter. The release rate of these dispensers, expressed in terms of the release rate versus time and the cumulative amount released versus time, are shown in Figures 8A and 8B. In the figures, the dashed lines repre-sent theoretical values and the solid lines represent actual values.
Dispensers were prepared as in Example 3 except that sorbitol was used in place of ammonium chloride. The release kinetics of these dispensers are presented in Figures 9A and 9B, with the dashed lines representing theoretical values and the solid lines representing actual values.
Three sets of dispensers were made according to the general procedure of Example 3 using procainamide hydrochloride as drug composition and ammonium chloride as osmagent. The original coating about the osmagent body was 125 microns thick and was made of cellulose acetate, 36.4% acetyl content. The final coating about the coated osmagent-drug assembly was made from cellulose acetate, 34.5% acetyl content and was 100, 150, and 200 microns thick, respPctively. The release rate of each set was determined as above and is plotted in Fig. 10, with .
' -15-the line connecting the circles designating the 100 micron thick final coating set, the line connecting the squares the 150 micron thick final coating set, and the line connecting the triangles the 200 micron thick final coating set.
A dispenser for administering progesterone was made as follows. Two mg of progesterone was mixed with 10 mg of pectin and 83 mg of sorbitol and the mixture was placed in the die cavity of a Manesty D-3b tableting machine and pressed slightly. Next, 60 mg of poly(ethylene oxide) was added to the die cavity and slight compression was applied to press it against the drug composition. The 100 mg of sorbitol was added to the die and the contents of the die were compressed to form a 1.1 cm diameter taolet comprising a drug composition separ-ated from osmagent ~y a poly(ethylene oxide) membrane. The tablet was then coated in an air suspension coater with a 270 micron thick film of 95% cellulose acetate having an acetyl content of 38.3%, and 5% polyethylene glycol (MW 400). The cellulose acetate film was coated from a 5% solution compris-ing 70% methylene chloride 30%~methanol. Finally, the coated assembly was heated for 1 hr at 80C, and after cooling to room temperature a 625 micron diameter passageway was drilled through the cellulose acetate film into the drug. The dispenser released 180 mcg of progesterone per hour, for 10 hrs, with a total release over this 10 hour period of 85%.
`` lO9Z~69 .
A dispenser for administering theophylline orally was prepared as follows. A drug composition was made by thoroughly blending 50 mg of theophylline having a solubility of about 8 mg/ml in water at 25C with 405 mg of sorbitol, 45 mg of pectin and 5 mg magnesium stearate. The composition was charged into the round die of a Manesty D-3b tableting machine and slight compression was applied to lightly compact it. Then, 80 mg of poly(ethylene oxide) having a MW of 4,000,000 was added to the die on top of the drug composition, spread across the compo-sition, and slight compression was applied against the coated composition. Next, an osmagent composition was prepared by blending 196 mg of mannitol, 22 mg of polyethylene glycol (MW 6000), and 2 mg of magnesium stearate. This blend was added to the die on top of the poly(ethylene oxide), and the contents of the die~were compressed to form a 1.1 cm diameter tab}et. The tablet was then coated in an air suspension coater with a mix of 95% cellulose acetate having an acetyl content of 329 and 5% polyethylene glycol (MW 400) in acetone and water (15% solution) until a layer 150 microns thick was formed about the drug - osmagent assembly. The coated assembly was placed in an oven for 1 hr at 80C thereby melting the poly(ethylene oxide) to form a hot, continuous melt adhering to the cellulose acetate at their points of contact. Then a 875 micron diameter passageway was drilled through the cellulose acetate wall into the drug. The average drug release rate from these dispensers was determined to be 4 mgjhr over 12 hr. Seventy percent of the drug was released over that period.
describes an osmotically driven drug dispenser that consists of a rigid housing~ a flexible partition that divides the housing interior into two compartments, a flowable drug composition filling one of the compartments, an osmotically effective solute within the other compartment, and an outlet passageway through the housing into the drug-conta;n;ng compartment. The portion of the housing that defines the osmotically effective solute-con-taining compartment is semipermeable; whereas the portion that defines the drug-containing compartment is impermeable. When placed in a water-contain-ing enviroDment, water is imbibed through the semipermeable portion of the housing into the solute-containing compartment causing that compartment to increase in volume by stretching the flexible partition and displacing it into the drug-containing ~on~rtment. Such displacement forces the flowable drug composition from the dispenser via the outlet.
United States 3,916,899 issued November 4,1975 to ALza Corp.
describes an osmotically driven drug dispenser that consists of a rigid, semipermeable housing whose interior is filled with an osmotically effect-ive drug compositionO The housing has a specifically sized out-~et passage-way through it. When the dispenser is placed in a water-containing environ-ment, water permeates through the semipermeable housing and dissolves thedrug composition. The osmotic imbalance between the resulting solution and the liquid in the environment causes water to be imbibed into the housing interior thus creating pressure therein which forces the drug solution into the enviroDment ~ia the outlet passageway.
~09Z469 The invention is an osmotically driven dispenser for use in a liquid-containing environment aomprising: a substantially rigid housing, a movable partition within the housing that divides the housing interior into a first c~rpartment and a seoond comparbncnt, with the portion of the housing that defines the first cYmpartment having an outlet passageway and the portion of the housing that defines the seaond ccnpartment being semi-permeable; active agent aomposition aontained within and filling the first compmrtment; and an osmotically effective aomposition in the second coopartment that imbibes liquid from the environment thnough the housing into the seaond comparbment causi~g pressure to be exerted on the movable partitian and active agent aomposition to be displaced from the first aom~
partment in response to that pressure through the outlet into the enviranment, characterized in that the portian of the housing that defines the first ccmpartment is semipermeable and the active ag nt composition is in a nonflcwable form ;n;tially and is osmotically effective such that liquid is imbibed fram the environment into the first coLparbment to aonvert the active agent aompositian into a flowable farm and the mass rate at which active agent aomposition is dispensed is a functian of the oombined vol~me rates of liquid imbibitian into the first and seaond a mpartJents.
The inventian also includes a process far making the above described dispenser characterized by forming one of either the active agent aomposLtion or the osmotically effec-tive aomposition into a body of predetermined shape, aoating a 1092~69 surface of said body with a flexible material to form the partition, forming the other of said compositions into a body of predetermined shape, attaching the bodies at said surface, coating the attached bodies,with a semipermeable material to form the housing, and forming the outlet passageway in the housing.
-The drawings illustrate several embodiments of theinvention and depict graphically their performance. In the - drawings:
Figure lA is an isometric view of a dispenser accord-ing to the invention designed for orally administering drugs;
Figures lB - lF are sectional views of the dispen~ser of Figure lA illustrating the dispenser at various stages in its operation;
: : .
Figure 2 is a sectional view of another embodiment of the invention designed for the same use as the dispenser of ~ Fig. lA;
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Figure 3 is a sectional view of yet another embodiment of the invention designed for the same use as the dispenser of Fig. lA;
Figure 4 is a side elevational view, partly in section, of an embodiment of the invention that is designed for releas-ing dEug in the vaginal cavity;
"- 109Z469 Figure 5 is a front view of a human eye with an ocular embodiment of the invention in operative position in the eye;
Figure 6 is a graph showing the actual and theoretical release rates of the dispensers of Example 1.
Figure 7 is a graph showing the actual and theoretical release rates of the dispensers of Example 2.
Figures 8A and 8B are graphs illustrating the perform-ance of the dispensers of Example 3.
Figures 9A and 9B are graphs illustrating the perform-ance of the dispensers of Example 4; and Figure 10 is a graph showing the actual and theoretical release rates of the dispensers of Example 5.
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- In the drawings and specification, like parts in related - figures are identified by like numbers.
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. In Figures lA through lF, the dispenser is generally designated 10. Dispenser 10 consists of a housing 11 formed by a semipermeable wall 12 that partly defines the perimeters of a first compartment 13 and a second compartment 14. Housing 11 has an ouelet passageway 15 in it that extends from compartment _5_ ~
... ., ~
~., . . " . . -` `" lO9Z469 13 to the exterior of dispenser 10. The remainders of the perimeters of compartme~ts 13 and 15 are defined by a flexible membrane 18. ~embrane 18 separates the compartments and forms a common wall or partition therebetween. Compartment 13 is filled with an initially nonflowable drug composition 16 that in solution exhibits an osmotic pressure gradient across wall 12 against the gastrointestinal fluids (that is, the osmotic pressure of drug composition 16 in solution is greater than the osmotic pressure of the gastrointestinal fluids. Sucn compositions that exhibit greater osmotic pressure than the environment liquid are said to be "osmotically effective~.) The osmotic effectiveness of drug composition 16 may be attributable to the drug itself and/or to one or more added osmotically effective compounds (hereinafter called Uosma-gents~). Compartment 14 is filled with one or more osmagents 17. ~embrane 18 is free of passageways and is formed of a flexible material that can stretch or distend from an initial unstretched position (Figure lB) through partly stretched positions (Figures lC through lE) to a fully stretched position (Figure lF).
Dispenser 10 operates in the following manner. Once it is swallowed, water 19 from the gastrointestinal fluid permeates through wall 12 into compartments 13 and 14 to dissolve the soluble components of drug composition 16 and osmagent 17, respectively, therein. The dissolving of drug composition 16 forms a flowable solution or slurry thereof.
Further water is imbibed into each compartment due to the lO9Z~69 osmotic pressure gradients between ~he gastrointestinal fluid and the respective solutions of drug composition 16 and osmagent 17. The rates at which water is so imbibed into the compart-ments will depend upon the water permeability of wall 12 and the magnitudes of said gradients. The water imbibed into compa~tment 14 exerts pressure on flexible membrane 18 causing it to stretch and displace into compartment 13, thereby forcing the solution or slurry of drug composition out of compartment 13 via passageway 15. The displacement of membrane 18 into compartment 13 continuously diminishes the volume of compartment 13 as shown in Figs. lC - lF. This continuous diminishment of volume keeps the solution of drug composition at saturation concentration, which, in turn, keeps the osmotic pressure gradient between the solution and the gastrointestinal fluid constant. This is especially important in instances in which the drug involved is highly soluble in water. The continuous imbibition of water into compartment 13 contributes to forcing the solution or slur`ry of drug composition 16 therefrom.
Accordingly, drug composition 16 is transformed within compart-ment 13 from a solid or other nonflowable form, e.g. gel, paste, or semisolid, into a flowable solution or slurry and is pumped from compartment 13 in response to the displacement of membrane 18 and the influx of water into compartment 13 through semipermeable wall 12. The combined force exerted by the displacement of membrane 18 and the influx of water into compartment 13 facilitates the dispensing of slurries from compartment 13, such as are formed when the drug is highly water insoluble.
.
. ARC 551 lO9Z469 Figures 2 and 3 depict other embodiments of the invention that are similar to dispenser 10 of Figures lA - lF in structure and operation, except as regards the configurations of the housing and of the membrane that divides the housing interior into the drug composition and osmagent compartments. Figure 2 illustrates an ellipsoidally-shaped dispenser 10 in which a greater portion of the perimeter of drug composition compartment 13 is defined by mem~rane 18. Figure 3 depicts a substantially parallelipiped-shaped dispenser 10 in which an even greater portion of the perimeter of the drug composition compartment 13 is defined by membrane 18.
Figure 4 shows a vaginal dispenser 10 designated for placement in a vagina. Dispenser 10 has an elongated, cylin-drical, self-sustaining shape with a rounded lead end 20 and a trailing end 21. It is equipped with a cord 22 for easily removing it from a vagina. Vaginal dispenser 10 is structur-ally and operationally similar to the dispensers of Figures 1 -3. Membrane 18 is shown at various stages of displacement (designated 18a - 18c) in Figure 4.
.
Figure 5 shows an ocular dispenser 10 in operative position in an eye 25. Ocular dispenser 10, except for its size and shape, is structurally and functionally identical to dispenser 10 of Figs. lA - lF. Eye 25 includes an upper eyelid 26 with eyelashes 27, a lower eyelid 28 witn eyelashes 29, and an eyeball 30 covered for the greater part by sclera 31 and at its center area by cornea 32. Eyel-ids 26 and 28 are lined with palpebral conjunctiva, and sclera 31 is lined with a bulbar conjunctiva that covers the exposed surface of eyeball 30. The portion of the palpebral conjunctiva which linès upper eyelid 1092~6~
26 and the underlying portion of the bulbar con~unctiva defines an upper cul-de-sac, while that portion of the palpebral con-junctiva which lines lower eyelid 28 and the underlying portion of the bulbar conjunctiva defines a lower cul-de-sac. Ocular dispenser 10 is designed for placement in the upper or lower cul-de-sac and its drug compartment contains an ophthalmic drug for release to eye 25 at a controlled and continuous rate over a prolonged period of time.
As illustrated by Figures 1 - 5, the invention can take a wide variety of shapes, sizes and forms for delivering drug to different body sites. The invention also can be sized, shaped and adapted for delivering appropriate active agents to streams, aquariums, fields, chemical reactions, anâ other liquid-containing environments of use.
In drug dispensing embodiments of the invention, wall 12 should be made from a material that is biologically compat-ible with the body site at which the dispenser is to be placed, permeable to water, and impermeable to the drug composition and osmagent, The material may be nonerodible or erodible but must maintain its rigid integral structure during the dispens-ing lifetime of the dispenser. Such materials include cellulose acetate, cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, cellulose diacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, poly-urethane, sulfonated polystyrenes, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbamate, cellulose acetate chloroacetate, cellulose dipalmitate, _g_ cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate, cellulose acetate valerate, cellulose acetate succinate~ cellulose propionate succinate, methyl cellulose, cellulose acetate p-toluene sulfonate, and cellulose acetate butyrate. Generally, these materials will have a water permeability of 10 5 to 10 1 cc mil/cm2 hr atm expres-sed per atmosphere by hydrostatic pressure difference across wall 12 at the temperature of use. Wall 12 will usually be about 150 to 450 microns thick, preferably 2~0-300 microns thick.
Membrane 18 may be formed ~rom the same materials as wall lo 12 or from known flexible polymers. When membrane 18 is made from lG the same material as wall 12 it may be made flexibl~ by (1) control-ling its thickness to about 50 to 200 microns~ and (2) by optionaIly adding from 0.01% to 40% of a suitable plasticizerO In such instances there may be water passage through membrane 18 from one of the com-partments 13, 14 to the other depending upon the particular drug com-position and osmagnet that are employed.
Passageway 15 should have the same dimensions as the pas-sageways of the dispensers described in United States 3,916,899 issued November 4, 1975 to ALza Corp~ Procedures for forming such passageways are described in United States 3,916,899 issued Novem-ber 4, 1975 to ALza Corp. and United States 4,016,880 issued April 12, 1977.
As indicated above~ compounds that may be used as osmagnets in the invention must exhibit an osmotic pressure in solution that is signi~ica~ ygreater than that of the ~` lO9Z~69 environment liquid. Thus, in drug dispensing embodiments the osmotic pressure of the solution of osmagent will be in excess of about 750 kPa. Osmagents useful in such embodiments include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, calcium carbonate, sodium sulfate, calcium sulfate, potassium acid phosphate, calcium lactate, d-mannitol, urea, inositol, magnesium succinate, tar-taric acid, starches, and carbohydrates such as raffinose, succrose, glycose, and mixtures thereof.
- The term "active agent" as used herein includes any compound, composition of motter or mixture thereof that can be delivered from tne dispenser to produ.ce a beneficial and useful result. Active agents include pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, a~ti-oxidants, plant growth promoters, plant growth inhi~itors, preservatives, anti-preservatives, dis-infectants, sterilization agents, catalysts, chemical reactants, fermentation agents, foods, food supplements, nutrients, cos-metics, drugs, vitamins, sex sterilants, fertility inhibitors, fertility promoters, air purifiers, micro-organism attenuators, and other agents that benefit the environment of use. The term ~drug~ as used herein includes any physiologically or pharma-cologically active substance that produces a localized or systemic effect in animals, including humans.
`` ~09Z~69 The invention dispensers may be manufactured by the following techniques. Active agent composition 16 is formed into a solid, semi-solid or pressed state by conventional methods such as ballmilling, calendering, stirring or roll-milling followed by pressing or tableting into a body of preselected shape. A semipermeable wall is then formed about the body of active agent composition by molding, spraying, or dipping. Alternatively the wall can be cast or otherwise formed and then filled with composition 16 and closed. A
portion of this wall constitutes membrane 18. Osmagent 17 is then pressed or formed into a body of preselected shape and is attached by adhesives or other joining techniques to the walled active agent composition. Finally, the resulting assembly is then surrounded by molding, spraying, or dipping with semipermeable wall 12. Passageway 15 may be formed in the portion of the wall about the active agent composition by the methods described in U.S. 3,916,-899. Of course, the above technique may be carried out by first forming a walled osmagent body, attaching a body of an active agent composition thereto, surrounding the resulting assembly with a semiperme-able material, and forming passageway I5. Alternatively both bodies can be surrounded by a semipermeable wall and the two walled bodies joined together by an adhesive.
:
Another manufacturing process involves charging layers of the active agent composition, flexible material, and osmagent into the die of a tabletting machine, compressing the three layers into a composite tablet, coating the composite tablet with a semipermeable material, and forming the outlet passage-way in the coating.
`" 109Z~69 The following examples illustrate further embodiments of the invention and are not intended to limit the invention in any manner. Unless otherwise indicated, percentages are by weight.
EXA~PLE 1 A dispenser for delivering the antiarrhythmic and antifibrillatory drug procainamide hydrochloride to the gastro-intestinal tract was manufactured as follows: 225 mg of pro-cainamide hydrochloride was pressed into a solid mass in a commercially available Manesty tableting machine to a Stoke's hardness of 8 kg. Next, the mass was coated in a standard air suspension machine with a film formed from a 5% solution of cellulose acetate having an acetyl content of 32~. The solution was made by dissolving 155 g cellulose acetate in a mixed sol-vent system of 3300 ml acetone and 330 ml water. The freshly formed film had a thickness of 125 microns.
Next, 350 mg of sodium chloride was pressed in the ~anesty machine to a Stoke's hardness of 8 kg. The pressed sodium chloride had a shape identical to the shape of the pressed procainamide hydrochloride. Then, a small drop of liquid cellulose acetate was spread onto one surface of the pressed sodium chloride and this surface was placed against a corresponding surface of the film-coated procainamide hydro-chloride. The two united masses were then coated in the air suspension machine with cellulose acetate per the above method to a wall thickness of 250 microns. Finally, an osmotic passageway having a diameter of 250 microns was drilled through the coating facing the procainamide hydrochloride using a CO2 la`ser.
. ''' ~' . ARC 551 `` 109Z~69 The release rate of procainamide hydrochloride was mea-sured according to known procedures by placing them in water with agitation and periodically determining the concentration of the drug in the water by spectrophotometric analysis.
Release rates were calculated from these measurements. Fig.
6 plots the release rate versus time, with actual release shown by a solid line and theoretical release by a dashed line.
Dispensers were made as in Example 1, except that the membrane separating the procainamide hydrochloride and the sodium chloride had a thickness of 190 microns and the wall had a thickness of 190 microns. The release rate of these dispensers was determined by the procedure described in Example 1. me resùlts are shown in Figure 7, with actual release rate designated by a solid line and theoretical release rate designated by a dashed line.
The general procedure of Example 1 was used, with the variations indicated below, to make other dispensers for admin-istering procainamide hydrochloride orally. The procainamide hydrochloride body was coated with a 75 micron thick film formed ` from a 5% solution of 70% cellulose acetate having an acetyl content of 38.3%, and 30% polyethylene glycol having a molec-ular weight of 400 dissolved in a 80:20 by weight methylene chloride-methanol solvent system, and then bonaed to a pressed 109~46~
body of ammonium chloride. The two bodies were finally coated with the cellulose acetate solution of Example 1 to form an exterior wall having a thickness of 90 microns. The outlet passageway was 200 microns in diameter. The release rate of these dispensers, expressed in terms of the release rate versus time and the cumulative amount released versus time, are shown in Figures 8A and 8B. In the figures, the dashed lines repre-sent theoretical values and the solid lines represent actual values.
Dispensers were prepared as in Example 3 except that sorbitol was used in place of ammonium chloride. The release kinetics of these dispensers are presented in Figures 9A and 9B, with the dashed lines representing theoretical values and the solid lines representing actual values.
Three sets of dispensers were made according to the general procedure of Example 3 using procainamide hydrochloride as drug composition and ammonium chloride as osmagent. The original coating about the osmagent body was 125 microns thick and was made of cellulose acetate, 36.4% acetyl content. The final coating about the coated osmagent-drug assembly was made from cellulose acetate, 34.5% acetyl content and was 100, 150, and 200 microns thick, respPctively. The release rate of each set was determined as above and is plotted in Fig. 10, with .
' -15-the line connecting the circles designating the 100 micron thick final coating set, the line connecting the squares the 150 micron thick final coating set, and the line connecting the triangles the 200 micron thick final coating set.
A dispenser for administering progesterone was made as follows. Two mg of progesterone was mixed with 10 mg of pectin and 83 mg of sorbitol and the mixture was placed in the die cavity of a Manesty D-3b tableting machine and pressed slightly. Next, 60 mg of poly(ethylene oxide) was added to the die cavity and slight compression was applied to press it against the drug composition. The 100 mg of sorbitol was added to the die and the contents of the die were compressed to form a 1.1 cm diameter taolet comprising a drug composition separ-ated from osmagent ~y a poly(ethylene oxide) membrane. The tablet was then coated in an air suspension coater with a 270 micron thick film of 95% cellulose acetate having an acetyl content of 38.3%, and 5% polyethylene glycol (MW 400). The cellulose acetate film was coated from a 5% solution compris-ing 70% methylene chloride 30%~methanol. Finally, the coated assembly was heated for 1 hr at 80C, and after cooling to room temperature a 625 micron diameter passageway was drilled through the cellulose acetate film into the drug. The dispenser released 180 mcg of progesterone per hour, for 10 hrs, with a total release over this 10 hour period of 85%.
`` lO9Z~69 .
A dispenser for administering theophylline orally was prepared as follows. A drug composition was made by thoroughly blending 50 mg of theophylline having a solubility of about 8 mg/ml in water at 25C with 405 mg of sorbitol, 45 mg of pectin and 5 mg magnesium stearate. The composition was charged into the round die of a Manesty D-3b tableting machine and slight compression was applied to lightly compact it. Then, 80 mg of poly(ethylene oxide) having a MW of 4,000,000 was added to the die on top of the drug composition, spread across the compo-sition, and slight compression was applied against the coated composition. Next, an osmagent composition was prepared by blending 196 mg of mannitol, 22 mg of polyethylene glycol (MW 6000), and 2 mg of magnesium stearate. This blend was added to the die on top of the poly(ethylene oxide), and the contents of the die~were compressed to form a 1.1 cm diameter tab}et. The tablet was then coated in an air suspension coater with a mix of 95% cellulose acetate having an acetyl content of 329 and 5% polyethylene glycol (MW 400) in acetone and water (15% solution) until a layer 150 microns thick was formed about the drug - osmagent assembly. The coated assembly was placed in an oven for 1 hr at 80C thereby melting the poly(ethylene oxide) to form a hot, continuous melt adhering to the cellulose acetate at their points of contact. Then a 875 micron diameter passageway was drilled through the cellulose acetate wall into the drug. The average drug release rate from these dispensers was determined to be 4 mgjhr over 12 hr. Seventy percent of the drug was released over that period.
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An osmotically driven dispenser suitable for use in a liquid-containing environment comprising: a substantially rigid housing, a movable partition within the housing that divides the housing interior into a first compartment and a second compartment, with the portion of the housing that defines the first compartment having an outlet passageway and the portion of the housing that defines the second compartment being semipermeable; active agent composition contained within and filling the first compartment;
and an osmotically effective composition in the second compartment that imbibes liquid from the environment through the housing into the second compartment causing pressure to be exerted on the movable partition and active agent composition to be displaced from the first compartment in response to that pressure through the outlet into the environment, characterized in that the portion of the housing that defines the first compartment is semipermeable and the active agent composition is in a non-flowable form initialy and is osmotically effective such that liquid is imbibed from the environment into the first compart-ment to convert the active agent composition into a flowable form and the mass rate at which active agent composition is dispensed is a function of the combined volume rates of liquid imbib?tion into the first and second compartments.
and an osmotically effective composition in the second compartment that imbibes liquid from the environment through the housing into the second compartment causing pressure to be exerted on the movable partition and active agent composition to be displaced from the first compartment in response to that pressure through the outlet into the environment, characterized in that the portion of the housing that defines the first compartment is semipermeable and the active agent composition is in a non-flowable form initialy and is osmotically effective such that liquid is imbibed from the environment into the first compart-ment to convert the active agent composition into a flowable form and the mass rate at which active agent composition is dispensed is a function of the combined volume rates of liquid imbib?tion into the first and second compartments.
2. The dispenser as claimed in Claim 1 further character-ized in that the entire housing is made of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.
3. The dispenser as claimed in Claim 1 further characterized in that the movable partition is movable by virtue of its flexibility and said pressure causes the partition to stretch and displace into the first compartment, thus diminishing the volume of the first com-partment.
4. The dispenser as claimed in Claim 3 further characterized in that the partition is make of cellulose acetate or poly (ethylene oxide).
5. The dispenser suitable for use in a body site as claimed in Claim 1 further characterized in that the liquid is water, and the active agent is a drug.
6. The dispenser as claimed in Claim 5 further characterized in that it is suitable for use in the gastrointestinal tract.
7. The dispenser as claimed in Claim 5 or 6 further character-ized in that the drug is highly water-soluble.
8. The dispenser as claimed in Claim 5 or 6 further character-ized in that the drug is highly water-insoluble.
9. A process for making the dispenser of Claim 1 characterized by forming one of either the active agent composition or the osmot-ically effective composition into a body of predetermined shape, coating a surface of said body with a flexible material to form said partition, forming the other of said compositions into a body of predetermined shape, attaching the bodies at said surface, coating the attached bodies with a semipermeable material to form said housing, and forming said outlet passageway.
10. The process as claimed in claim 9 further characterized in that the bodies are formed, said surface is coated with a flexible material and the bodies are attached by charging layers of the active agent com-position, flexible material, and osmotically effective composition into a die and compressing the layers into a composite body.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US743,975 | 1976-11-22 | ||
| US05/743,975 US4111202A (en) | 1976-11-22 | 1976-11-22 | Osmotic system for the controlled and delivery of agent over time |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1092469A true CA1092469A (en) | 1980-12-30 |
Family
ID=24990933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA291,085A Expired CA1092469A (en) | 1976-11-22 | 1977-11-17 | Osmotically driven active agent dispenser and process for making same |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4111202A (en) |
| JP (1) | JPS5364678A (en) |
| AR (1) | AR217457A1 (en) |
| AT (1) | AT359181B (en) |
| AU (1) | AU510115B2 (en) |
| BE (1) | BE861031A (en) |
| CA (1) | CA1092469A (en) |
| CH (1) | CH625955A5 (en) |
| DE (1) | DE2751587A1 (en) |
| DK (1) | DK153366C (en) |
| ES (1) | ES464251A1 (en) |
| FR (1) | FR2371224A1 (en) |
| GB (1) | GB1551898A (en) |
| IE (1) | IE45908B1 (en) |
| IL (1) | IL53412A0 (en) |
| IT (1) | IT1091613B (en) |
| MX (2) | MX167436B (en) |
| NL (1) | NL189848C (en) |
| SE (1) | SE440724B (en) |
| ZA (1) | ZA776896B (en) |
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| US3247066A (en) * | 1962-09-12 | 1966-04-19 | Parke Davis & Co | Controlled release dosage form containing water-swellable beadlet |
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| US3828777A (en) * | 1971-11-08 | 1974-08-13 | Alza Corp | Microporous ocular device |
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-
1976
- 1976-11-22 US US05/743,975 patent/US4111202A/en not_active Expired - Lifetime
-
1977
- 1977-11-01 GB GB45417/77A patent/GB1551898A/en not_active Expired
- 1977-11-07 IE IE2269/77A patent/IE45908B1/en not_active IP Right Cessation
- 1977-11-10 DK DK499377A patent/DK153366C/en not_active IP Right Cessation
- 1977-11-11 NL NLAANVRAGE7712463,A patent/NL189848C/en not_active IP Right Cessation
- 1977-11-15 AU AU30647/77A patent/AU510115B2/en not_active Expired
- 1977-11-16 IL IL53412A patent/IL53412A0/en not_active IP Right Cessation
- 1977-11-17 AT AT822177A patent/AT359181B/en active
- 1977-11-17 FR FR7734568A patent/FR2371224A1/en active Granted
- 1977-11-17 ES ES464251A patent/ES464251A1/en not_active Expired
- 1977-11-17 CA CA291,085A patent/CA1092469A/en not_active Expired
- 1977-11-18 DE DE19772751587 patent/DE2751587A1/en active Granted
- 1977-11-18 ZA ZA00776896A patent/ZA776896B/en unknown
- 1977-11-18 AR AR270027A patent/AR217457A1/en active
- 1977-11-21 CH CH1419477A patent/CH625955A5/de not_active IP Right Cessation
- 1977-11-21 SE SE7713119A patent/SE440724B/en not_active IP Right Cessation
- 1977-11-21 JP JP13900477A patent/JPS5364678A/en active Granted
- 1977-11-21 IT IT69628/77A patent/IT1091613B/en active
- 1977-11-21 BE BE182795A patent/BE861031A/en not_active IP Right Cessation
- 1977-11-22 MX MX595377A patent/MX167436B/en unknown
- 1977-11-22 MX MX776867U patent/MX6436E/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE7713119L (en) | 1978-05-23 |
| ES464251A1 (en) | 1978-12-16 |
| IE45908B1 (en) | 1982-12-29 |
| IT1091613B (en) | 1985-07-06 |
| BE861031A (en) | 1978-03-16 |
| CH625955A5 (en) | 1981-10-30 |
| GB1551898A (en) | 1979-09-05 |
| MX167436B (en) | 1993-03-23 |
| AU510115B2 (en) | 1980-06-05 |
| IE45908L (en) | 1978-05-22 |
| FR2371224A1 (en) | 1978-06-16 |
| NL189848B (en) | 1993-03-16 |
| SE440724B (en) | 1985-08-19 |
| ZA776896B (en) | 1978-09-27 |
| FR2371224B1 (en) | 1980-12-12 |
| ATA822177A (en) | 1980-03-15 |
| AR217457A1 (en) | 1980-03-31 |
| JPS61803B2 (en) | 1986-01-11 |
| NL7712463A (en) | 1978-05-24 |
| DE2751587C2 (en) | 1987-03-26 |
| DK499377A (en) | 1978-05-23 |
| DK153366B (en) | 1988-07-11 |
| AU3064777A (en) | 1979-05-24 |
| IL53412A0 (en) | 1978-01-31 |
| DK153366C (en) | 1988-12-27 |
| DE2751587A1 (en) | 1978-05-24 |
| JPS5364678A (en) | 1978-06-09 |
| MX6436E (en) | 1985-05-31 |
| NL189848C (en) | 1993-08-16 |
| AT359181B (en) | 1980-10-27 |
| US4111202A (en) | 1978-09-05 |
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