Osmotic device
12 claims: 2 independent, 10 dependent
- 1Patentkrav 1. Anordning för avgivande av en kontrollerad mängd välgörande medel per tidsenhet till en användningsomgivning, vilken anordning kännetecknas av:a) en vägg formad i åtminstone en del av en komposition genomtränglig för passage av en yttre vätska närvarande i användningsomgivningen, vilken vägg omger och bildar b) ett rum;c) en första komposition i rummet, nämnda första komposition bestående av ett välgörande medel och en osmotiskt verksam polymer;d) en andra komposition i rummet, nämnda andra komposition bestående av ett osmotiskt verksamt medel och en osmotiskt verksam polymer och e) en passage i väggen kommunicerande med den första kompositionen och anordningens yttre för avgivande av det välgörande medlet från anordningen.
- 2Anordning för avgivande av en kontrollerad mängd välgörande medel per tidsenhet enligt kravet 1, kännetecknad av att den väggen bildande kompositionen består av ett antal ämnen valda ur den grupp, som består av cellulosaacylat, cellulosadiacylat, cellulosatriacylat, cellulosaacetat, cellulosadiacetat, cellulosatriacetat, etylcellulosa, cellulosaacetatbutyrat, cellulosaacetatpropionat, hydroxipropylmetylcellulosa, hydroxilägrealkylcellulosa, metylcellulosa, metyletylcellulosa och blandningar därav.
- 3Anordning för avgivande av en kontrollerad mängd välgörande medel per tidsenhet enligt krav 1, kännetecknad av att den första kompositionen i rummet är ett skikt och den andra kompositionen i rummet är ett skikt.
- 4Anordning för avgivande av en kontrollerad mängd välgörande 455 918 medel per tidsenhet enligt krav 1, kännetecknad av att den första kompositionen insuger yttre vätska genom väggen in i rummet och att den andra kompositionen insuger yttre vätska genom väggen in i rummet.
- 5Anordning för avgivande av en kontrollerad mängd välgörande medel per tidsenhet enligt krav 1, kännetecknad av att den osmotiskt verksamma polymeren utgörande den andra kompositionen har en molekylvikt högre än den molekylvikt, som den osmotiskt verksamma polymeren har i den första kompositionen.
- 6Anordning för avgivande av en kontrollerad mängd välgörande medel per tidsenhet enligt krav 1, kännetecknad av att det välgörande medlet är ett läkemedel.
- 7Anordning för avgivande av en kontrollerad mängd välgörande medel till användningsomgivningen enligt krav 1, k ä η n e tecknad av att väggen är ett laminat bestående av ett semipermeabelt laminat och ett mikroporöst laminat.
- 8Anordning för avgivande av en kontrollerad mängd välgörande medel till användningsomgivningen per tidsenhet enligt krav 1, kännetecknad av att kompositionen bildande väggen innehåller polyetylenglykol.
- 9Anordning för avgivande av en kontrollerad mängd välgörande medel till användningsomgivningen enligt krav 1, k ä η n e tecknad av att den osmotiskt verksamma polymeren i den första kompositionen är polyetylenoxid.
- 10Anordning för avgivande av en kontrollerad mängd välgörande medel till användningsomgivningen enligt krav 1, k ä η n e tecknad av att den osmotiskt verksamma polymeren i den andra kompositionen utgöres av polyetylenoxid.
- 11Anordning för avgivande av en kontrollerad mängd välgörande medel till användningsomgivningen enligt krav 1, k ä η n e tecknad av att medlet i läkemedlet är nifedipin, verapamel, diltiazen, diklofenak, propanolol, proszin, ibuprofen, -455 918 44 . ketoprofen, haloperiodol, indometacin och cefalexin.
- 12Anordning för avgivande av en kontrollerad mängd välgörande medel per tidsenhet till användningsomgivningen enligt 5 krav 1, kännetecknad av att den första kompositionen utgöres av ett osmotiskt verksamt medel. 455 918 455 918 VIKTPROCENT ÖKNING
Independent claims12
234 paragraphs in 3 sections, as filed
(24) Race day (62) National application number (86) International filing day (86) Filing date for European patent application (30)
80-08-22
84-11-12
84-05-09
84-05-09 (11) Publication number 3 10
Application received as ·
E Swedish patent application
O completed international patent application with number □ converted European patent application with number
5/5/11 US 493760 (71) Applicant Alza Corporation, Palo Alto Cal US (72) Inventor PS L. Wong, B. Barclay, J. C. Deters, F. Theeuwes
Hayward, Menlo Park, Mountain View, Los Altos Cal (74) Ombud H Albihns patent agency AB (54) Designation Osmotic dispensing device with dual thermodynamic effect (56) Published publications: --- (57) Summary:
An osmotic system is shown consisting of a wall formed of at least a portion of semipermeable material surrounding a room. The room contains a first osmotic composition consisting of a beneficial agent and a second and distinct osmotic composition. A passage in the wall connects the first composition with the exterior of the system.
DB 705293 AUF13S8 0M
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The numbers in brackets indicate international identification code, INID code Letter mom clamps indicates international document code
455 918
The present invention relates to both new and unique delivery systems. More particularly, the invention relates to an osmotic delivery device consisting of a wall at least partially formed of a semipermeable material surrounding a compartment consisting of: (1) a first osmotic composition comprising a beneficial agent, and preferably an osmotically active agent and / or an osmotically active polymer, said composition in contact with (2) a second osmotic composition consisting of an osmotically active agent and an osmotically active polymer. A passage through the wall connects the exterior of the osmotic device with the first osmotic composition containing beneficial agents for delivery of the first composition from the osmotic device. The osmotic device is useful for delivering beneficial agents which, due to their solubility, are difficult to dispense in a known manner with a controlled amount per unit time from an osmotic delivery system.
Background of the Invention
Since ancient times, both pharmacology and medicine have been searching for delivery systems for the administration of beneficial drugs.
The first written reference to a dosage form can be found in Eber Papyrus, 25 written around 1552 BC. Eber Papyrus mentions dosage forms such as anal suppositories, vaginal dispensers, liniments, oral pill preparations and other dosage preparations. About 2,500 years have passed without any success in the development of the dosage forms, when the Arab physician Rhazes, 865-925 AD. discovered the pill placed. About a century later, Persian Avicenna, 980-1037 AD, placed pills with gold or silver to increase the patient's ability to accept the drug and to improve the drug's effectiveness. Around this time, the first tablets of Arabic manuscripts written by al-Zahrawi were described,
936-1009 AD The manuscript describes tablets in the form of voids in two opposite tablet forms. Pharmacology and medicine waited about 800 years for the next invention of the dosage forms, when Mothes in 1883 invented the capsule for the administration of drugs. The next big step in the dosage forms came in 1972
455 918 The invention of the osmotic delivery device of Theeuwes and Higuchi, described in U.S. Patents
845 770 and 3,916,899. The osmotic delivery device according to these patents consists of a semi-permeable wall surrounding a room containing a useful agent. The wall is permeable to passage of outer fluid and substantially impervious to passage of useful agent. There is a passage through the wall for delivery of the useful agent from the osmotic device. These devices release useful agent by suctioning liquid through the semipermeable wall into the room at an amount per unit time determined by the permeability of the semipermeable wall and the osmotic pressure gradient through the semipermeable wall to provide an aqueous solution containing useful agent which is distributed. through the passage from the device. These devices are extremely effective in delivering useful agents that are soluble in liquid and exert an osmotic pressure gradient through the semipermeable wall to the outer fluid.
An epoch-making improvement of the osmotic delivery devices was presented the dispersion art by inventor Felix Theeuwes in U.S. Patent No. 4,111,202. useful agent and a room containing osmotically active agent separated by a membrane. This membrane is movable from a resting state to an expanded state. The osmotic device releases agents by sucking fluid through the semipermeable wall into the compartment containing osmotically active agent and provides a solution that causes the compartment to increase in volume and act as a driving force applied to the membrane.
This force forces the membrane to expand toward the space containing useful agent and decreases the corresponding volume in the space containing useful agent, whereby useful agent is dispensed through the passage from the osmotic device. While this device works successfully for its intended purpose and because it can deliver a large number of useful agents with different solubilities, its use can be limited due to the preparation of the device.
455 918 the steps and costs of making and placing the movable film in the room of the osmotic device.
U.S. Patent No. 4,327,725 discloses an osmotic dispensing device for delivering beneficial agents which, due to their solubility in aqueous and biological fluids, are difficult to dispense in meaningful amounts with a controlled amount per unit time. The osmotic device of this patent consists of a semipermeable wall surrounding a room containing beneficial agents which is insoluble to highly soluble in water and biological fluids in the presence of an external liquid entering the device thereby causing the beneficial the agent is dispensed through the passage from the device. This device works successfully for the intended purpose and it delivers many hard-earned charities for the intended purpose. It has now been observed that its use can be limited since the hydrogel lacks in-depth ability to absorb sufficient fluid for the maximum self-expansion required to extrude the beneficial agent from the device.
It will be appreciated by those skilled in the art of dispensing whether an osmotic device can be provided which exhibits a high degree of osmotic activity for delivery of a beneficial agent by generating in situ an expansion force sufficient to deliver a maximum amount of the agent with a controlled release per unit time. from the osmotic device, so that an osmotic device has a positive value and represents an advance in the art of dispensing. Similarly, it will be appreciated by those skilled in the art of dispensing immediately if an osmotic device is available possessing a dual thermodynamic osmotic activity for delivering increased amounts of a beneficial agent, said osmotic device will thereby have practical use in pharmacology and medicine.
Objects of the invention
Accordingly, in line with the above presentation, it is an immediate object of the present invention to provide an osmotic system which represents a further improvement in the dispersion art.
It is a further object of the invention to provide an osmotic system produced in the form of an in vivo delivery device for beneficial drugs which are difficult to deliver and can now be delivered from the osmotic device provided by the present invention in therapeutically effective amounts. for a fixed period of time.
It is a further object of the invention to provide an osmotic system having a dual osmotic activity, which system consists of a compartment containing a first osmotically active composition consisting of a drug and preferably an osmotically active agent and / or an osmotically active polymer and an osmotically active polymer. other osmotic composition consisting of an osmotically active agent and an osmotically active polymer, which composition cooperates for delivery of drugs from the osmotic device.
It is a further object of the present invention to provide an osmotic device provided with means for introducing large amounts of a water-insoluble or a small water-soluble drug and means for delivering the drug in both cases with a controlled amount per unit time and continuously for a prolonged period of time.
It is a further object of the invention to provide an osmotic device capable of delivering a pH-dependent beneficial agent by providing a neutral medium for delivery of the beneficial drug in a finely divided form for increasing the surface area and maximizing the amount of dissolution per unit time of the beneficial agent. agent.
It is a further object of the invention to provide an osmotic system for delivering a drug having a very low amount of dissolved drug per unit time as the limiting step for delivery of the drug from the system, but which can now be dispensed using an osmotic composition which functions in situ as a wetting agent and a solubilizing agent for increasing the amount of dissolution per unit time and the solubility of the drug, thereby improving the output of the osmotic system.
It is a further object of the present invention to provide an osmotic system consisting of means for maintaining a high level of osmotic activity for a polymer used to deliver a beneficial agent from the osmotic system.
It is a further object of the invention to provide an osmotic therapeutic device capable of administering a complete pharmaceutical dosage regimen consisting of poorly soluble to highly soluble agents with a controlled amount per unit time and continuously for a specific period of time, the use of which requires only the insertion of and possibly ending the regime.
Other objects, embodiments, views and advantages of the present invention will become apparent to those skilled in the art from the following detailed description in conjunction with the figures and the appended claims.
Brief description of the springs
In the figures, which are not drawn to scale, but intended to illustrate various embodiments of the invention, figures are shown as follows:
Figure 1 shows an isometric view of an osmotic device designed for oral administration of a beneficial agent to the gastrointestinal tract; Fig. 2 shows a cut view of the osmotic device of Fig. 1 illustrating the structure of the osmotic device of Fig. 1; Fig. 3 is a cut-away view of the osmotic device of Fig. 1 illustrating the osmotic device in function and releasing a beneficial agent from the osmotic device; Fig. 4 shows a cut view of the osmotic device of Fig. 1 which is also shown in Fig. 3, illustrating the osmotic device in function and dispensing a
455 918 greater amount of beneficial agent from the osmotic device; Fig. 5 shows an osmotic therapeutic device with its wall partially removed, arranged to deliver a beneficial agent to a body passage such as the anorectal and vaginal openings;
Figure 6 shows an osmotic device of Figure 5 with a different wall structure; Fig. 7 shows an osmotic device according to Fig. 5, where a wall structure other than that of Fig. 6 is drawn; Fig. 8 shows the weight of recovered material as a function of the time of a polymer encapsulated in a semi-permeable membrane when the encapsulated polymer is placed in water; Fig. 9 shows the cumulative amount of drug released from a device consisting of an osmotically active polymer with two different molecular weights; Fig. 10 shows the cumulative amount of drug released from a device using various types of osmotically active polymers; Fig. 11 shows an osmotic pressure curve for a number of osmotically active agents and a number of compositions of osmotically active polymers / osmotically active agents; Figure 12 shows a cumulative release profile for an osmotic system using two distinct osmotically active polymers;
Fig. 13 shows the release rate per hour for an osmotic system different from that of Fig. 9 and containing an osmotically active polymer with two different molecular weights; Fig. 14 shows the cumulatively released amount from a single composition layer consisting of a single layer; Figure 15 shows in vivo and in vitro cumulative release of a drug delivered from the osmotic device; Figure 16 shows in vivo and in vitro cumulative release of various drugs delivered by an osmotic device.
In the drawings and in the description, similar parts in related figures have been identified with equal numbering. The terms which appear earlier in the description and in the description of the drawings as well as embodiments thereof are further described elsewhere in the description.
<sup>35</sup>
Detailed description of the drawings
The figures give examples of various osmotic devices according to the invention, which are not intended to define the invention. An eczema
455 918 piles on such a device are seen in Fig. 1, where an osmotic device 10 is seen, consisting of a body 11 provided with a wall 12 and a passage 13 for releasing beneficial agents from the osmotic device 10.
In Figure 2, the osmotic device 10 of Figure 1 is shown in the cut section. In Fig. 2, the osmotic device 10 consists of a body 11, a semipermeable wall 12, which surrounds and forms an inner space 14 which communicates through a passage 13 with the exterior of the osmotic device 10. Room 14 contains a first osmotic composition consisting of a beneficial agent 15, represented by dots, and may be from insoluble to highly soluble in suction fluid in room 14, an osmotically active agent 16 represented by wave lines which is soluble in room 14 suction fluid and exhibiting an osmotic pressure gradient through the semipermeable wall 12 toward an outer liquid, and an osmotically active polymer 17, represented by horizontal bars, which sucks fluid into the space 14 and exerts an osmotic pressure gradient through the semipermeable wall 12 toward an outer fluid present in the use environment. The wall 12 is formed as a semi-permeable composition which is substantially permeable to passage of the surrounding liquid and substantially impervious to passage of the agent 15, the osmotically active agent 16 and the osmotically active polymer 17. The semipermeable wall 12 is non-toxic and maintains its physical and chemical form during the delivery time of the device 10.
The room 14 also houses a second osmotic composition at a distance from the passage 13 and in contact with the first composition. The second composition is an expandable driving force acting in conjunction with the first osmotic composition to deliver a maximum amount of beneficial agent 15 from the osmotic device 10. The second osmotic composition consists of an osmotically active agent 18 which is soluble in liquid penetrating into space 14 and exerts an osmotic pressure gradient through wall 12 toward the outer fluid, mixed with an osmotically active polymer 19, which sucks fluid into space 14 and exerts an osmotic pressure gradient through the wall 12 toward the outer fluid. The osmotically active polymers 17 and 19 are hydrophilic cotton 455
<img file="SE455918B_D0002.tif" />
<img file="SE455918B_D0003.tif" />
soluble or slightly crosslinked water-insoluble polymers and possesses osmotic properties, such as the ability to absorb outer liquid, exert an osmotic pressure gradient through the semipermeable wall to the outer liquid, and swell or expand in the presence of the liquid. The osmotically active polymers 17 and 19 are mixed with the osmotically active agents 16 and 18 for suction of maximum volume of outer fluid in the chamber 14. This liquid is available to the osmotically active polymers 17 and 19 to optimize the volumetric amount per unit time for total expansion of the osmotically active polymers 17 and 19. This means that the osmotically active polymers 17 and 19 absorb liquid suction in the space 14 by osmotic suction action of the osmotically active polymers 17 and 19 supported by the osmotic suction action of the osmotically active agents 16 and 18 to obtain a maximum expansion of the osmotically active polymers 17 and 19 to enlarged state.
In operation, the beneficial agent 15 is dispensed from the osmotic device 10 according to a presently preferred embodiment by (1) suctioning fluid through the first composition to form a suspension in situ and dispensing the suspension through the passage and simultaneously (2) suctioning the suspension. liquid of the second composition causing the second composition to swell and cooperate with the first composition to drive the medium suspension through the passage. According to the described function, the osmotic device can be treated as a cylinder, with the second composition expanding as well as the movement of a piston to assist in dispensing a suspension of the agent from the osmotic device. Although the shape of the osmotic device drawn in Figs. 1 and 2 is not a true cylinder, it is approximately enough for the following physical analysis. In this analysis, the volume per unit of time output from the osmotic device is F<sub>fc</sub> composed of two sources; the water intake amount per unit time of the first composition F and the water intake amount per unit time of the second composition 0, where:
<img file="SE455918B_D0004.tif" />
<img file="SE455918B_D0005.tif" />
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<img file="SE455918B_D0007.tif" />
(in)
455 918
While the boundary between the first composition and the second composition is very slightly hydrated during the operation of the osmotic device, there is a slight water migration between the compositions. Thus, the amount of water suction per unit time of the second composition Q is equal to the expansion of its volume, i.e.
P
--- = Q dt (2)
The total amount of delivery per unit of time from the osmotic device is then dm = F<sub>fc</sub> . C = (F + Q) C (3) where C is the concentration of the beneficial agent in the slurry delivered. Maintaining the volume V and surface area A of the osmotic device gives Equations 4 and 5:
V = V, + V ^ (4) dp
A = A, + V (5) dp where V, and V dp and the second composition, respectively, and where A is equal to the surface area of the composition and is equal to the volume of the first composition. , and A dp contact with the wall through the first second composition, respectively. In function, both increase with time, which
V and A with time, while V, and APP in the device provide beneficial agents.
reduces
The volume of the second composition, which expands over time, as the liquid is sucked into the room, is given by Equation 7:
<img file="SE455918B_D0008.tif" />
(7) where W is the weight of the suction fluid through the second composition and is the weight of the second composition initially
455 918 is present in the device, W<sub>hrs</sub>Is the ratio of liquid to original solids
In the one of the second compositions, the density of the second composition corresponds to the geometry of W ^ / W ^, where r is the radius: the surface is related to the volume of <as follows:
. Thus, based on a cylinder prior to the cylinder, the suction can swell the second composition
W _ £ e
W, (8)
A, = A α (9)
The amount of liquid suction per unit of time in each room is:
<img file="SE455918B_D0009.tif" />
<img file="SE455918B_D0010.tif" />
(10) (11) where k is equal to the osmotic permeability of the wall, h is equal to the thickness of the wall, Δ and is the osmotic gradients of the first composition and the second composition. The total output from the device is therefore:
<td></td><td>dm dt</td><td>kh</td><td>C</td><td>A</td><td>2 - no</td><td>2 Y</td><td>WP P</td><td><sup>W</sup>hrs 1 + - W ATTd P</td>
<td> 30</td><td>+ πγ<sup>2</sup> +</td><td>2 r</td><td>w _P P</td><td> 1</td><td>w P</td><td>Δπρ</td><td></td><td> (12)</td>
Figures 3 and 4 illustrate the osmotic device in function described for Figures 1 and 2. In Figures 3 and 4, in the osmotic device 10, liquid is sucked through the first composition 35 at an amount per unit time determined by the permeability of the the wall and the osmotic pressure gradient through the wall. The suction fluid continuously forms a solution containing beneficial agent or a solution or of a gel of osmotically active agent and osmotically active polymer containing well
455 918 suspending agent, which solution or suspension in each case is released by the combined action of the device
10th These mechanisms of action include the solution or suspension being osmotically delivered through the passage during continuous formation of solution or suspension and by swelling and increasing the volume of the second composition represented by the increase in height of the vertical lines of Figures 3 and 4. This subsequent swelling and increase in volume imposes pressure on the solution or suspension, thereby aiding the first composition and simultaneously causing delivery of the beneficial agent to the exterior of the device.
The first composition and the second composition work together to substantially ensure that the release of beneficial agents from the room is constant for an extended period of time in two ways. First, the first composition absorbs outer liquid through the wall, whereby either a solution or a suspension is formed, the latter will not substantially dispense in the zero order (without the second composition present), as the driving force decreases with time. Second, the second composition will operate through two simultaneous functions: first, the second composition acts to continuously concentrate the beneficial agent by suctioning some liquid from the first composition to keep the concentration of the beneficial agent from falling under saturation, and secondly, the second composition by suctioning external liquid through the wall continuously increasing its volume, thereby exerting a force on the first composition and reducing the volume of beneficial agents; thus directing the beneficial means of passage into the room. In addition, as the extra solution or suspension formed in the first compartment is squeezed out, the osmotic composition comes into close contact with the inner walls and creates a constant osmotic pressure and therefore a constant amount of delivery per unit time in conjunction with the second composition. The swelling and expansion of the second composition, with its accompanying increase in volume, together with the corresponding decrease in volume of the first composition, ensures that the release of beneficial agents takes place at a controlled amount per unit time.
455 918
The device 10 in Figures 1 to 4 can be made in many embodiments, including the presently presented embodiment for oral use, to release either a local or systemically acting therapeutic agent in the gastrointestinal tract. Oral systems 10 can have various conventional shapes and sizes such as rounds having a diameter of 0.5 to
1.3 cm. In these forms, the system 10 can be adapted to administer a beneficial agent to a large number of animals, including warm-blooded animals, humans, birds, reptiles and fish.
Figures 5, 6 and 7 show another embodiment, an osmotic device 10 formed for placement in a body passage, such as the vagina or anorectal canal. The device 10 has an extended cylindrical self-supporting mold with a rounded front end 20, a rear end 21 and this is equipped with manually controlled wires 22 for easy removal of the device 10 from a biological passage. The device 10 is structurally identical to the device 10 described above and operates in a similar manner. In FIG. 5 For example, the device 10 has been drawn with a semipermeable wall 23, in Fig. 6, with a laminated wall 24 consisting of an inner semipermeable laminate connected to the space 14, and an outer microporous laminate spaced from the space 14. In Fig. 7, the device 10 laminated wall 28 formed as a microporous laminate 29 adjacent to space 14 and a semipermeable laminate 30 adjacent to the use environment and in laminar arrangement with the microporous laminate 29. The device 10 provides a beneficial agent for absorbing the vaginal mucosa or anorectal mucosa to produce a local or systemic effect in vivo for an extended period of time.
The osmotic devices of Figures 1 to 7 can be used to deliver a large number of drugs with a controlled amount per unit of time regardless of the drug's pH dependency or where the amount of dissolution per unit time of the agent can vary from low to high in the liquid environment such as stomach acid and intestine. - <sub>r</sub> added liquids. The osmotic devices also provide high loading of low solubility agents and are delivered in a meaningful therapeutic amount. Although Figures 1 to 7 illustrate various osmotic devices which can be produced accordingly
455 In accordance with the invention, it is obvious that the devices cannot be considered limited therefrom, since the devices can have a large number of shapes and sizes for delivering beneficial agents to the environment of use. For example, the devices may include buccal, implantable, artificial glands, cervical, intrauterine, ears, nose, skin, subcutaneous and blood-giving devices. The devices can also be shaped and sized to deliver active agent into streams, aquariums, in fields, factories, reservoirs, laboratory spaces, greenhouses, transport devices, marine purposes, military purposes, hospitals, veterinary clinics, nursing homes, farms, zoos, chemical reactions and other uses.
Detailed description of the invention
In accordance with the practice of the present invention, it has now been found that osmotic delivery devices 10 can be produced with a first osmotic composition and a second osmotic composition simultaneously housed and in cooperative relationship in the device's room. The space is formed by a wall consisting of a material which does not seriously affect the beneficial agent, the osmotically active agent, the osmotically active polymer or the like. The wall is permeable to the passage of an outer liquid such as water and biological fluids and is substantially impervious to the passage of agents, osmotically active agents, osmotically active polymers and the like. The wall is formed of a material that does not adversely affect the animal or host and the selectively semipermeable material is used to form a wall that is non-erodible and insoluble in the liquid. Typical materials for making such walls are cellulose esters, cellulose ethers and cellulose ester ethers. These cellulose polymers have a degree of substitution, DS, of the anhydroglucose unit greater than 0 and up to 3. The degree of substitution refers to the average number of hydroxyl groups originally present in the anhydroglucose unit consisting of the cellulose polymer replaced by a substituting group. Representative materials include a number selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose
455 918 triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alcanylates, mono-, di- and tricellulose aroylates and the like. Examples of polymers include cellulose acetate with a DS up to 1 and an acetyl content up to 21%, cellulose acetate with an acetyl content of 32 to 39.8%, cellulose acetate with a DS of 1 to 2 and an acetyl content of 21 to 35%, cellulose acetate with a DS of 2 to 3 and an acetyl content of 35 to 44.8% and the like. More particular cellulose polymers include cellulose propionate having a DS of 1.8 and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%, cellulose acetate butyrate having a DS of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%, cellulose acetate butyrate with an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7 %, cellulose triacylates with a DS of 2.9 to 3, such as cellulose trivalent, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate and cellulose trioctanoate, cellulose diacylates with a DS of 2.2 to 2.6, such as cellulose disuccinate, cellulose losadipalmate, cellulose dioctanoate, cellulose dipental, cellulose esters such as cellulose acetate butyrate and cellulose acetate propionate and the like.
Additional semipermeable polymers include ethyl cellulose, cellulose nitrate, acetaldehyddimetylacetat, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, cellulose dimethylaminoacetate, semipermeable polyamides, semipermeable polyurethanes, semipermeable sulfonated polystyrenes, cross-linked selectively semipermeable polymers formed by the coprecipitation of a poly30 anion and a polycation as disclosed in U.S. U.S. Patent Nos. 3,173,876, 3,276,586, 3,541,005, 3 541 006 and 3,546,142; semipermeable polymers disclosed in U.S. Pat. No. 3,133,132, lightly crosslinked polystyrene derivatives, crosslinked poly (sodium styrene sulfonate), crosslinked poly (vinylbenzyl trimethyl 35 ammonium chloride), semipermeable polymers having a liquid content of 10 cm to 10 cm. atm) expressed -8 per atmosphere 10 hydrostatic or osmotic pressure difference through the semipermeable wall. The polymers are known according to US Patents 3,845,770, 3,916,899 and 4,160,020
455 918 and in the Handbook of Common Polymers by Scott, JR and Roff, WJ, (1971), published by CRC Press, Cleveland, Ohio, USA.
The laminated wall consisting of a semipermeable laminate and a microporous laminate is in laminar arrangement and these cooperate to form an integrated laminated wall which retains its physical and chemical integrity and does not separate into laminates during the intermediate release of the osmotic device. The semi-permeable laminate is made from semi-permeable polymeric materials mentioned above, the semi-permeable homopolymers, the semi-permeable copolymers and the like.
Microporous laminates suitable for making an osmotic device usually consist of preformed microporous polymeric materials and polymeric materials which can form a microporous laminate in the application environment. The microporous materials in both embodiments are laminated to form the laminated wall. The preformed materials suitable for forming microporous laminates are substantially inert, they retain their physical and chemical integrity during the release period, and may be generally described as having a sponge-like appearance which provides a supporting structure for a semi-permeable laminate and also provides a structural structure. for microscopic pores or cavities connected to each other. The materials may be isotropic, the structure being homogeneous through a cross-sectional surface, or may be anisotropic, the structure being inhomogeneous over a cross-sectional surface. The pores may be continuous pores having apertures in both surfaces of the microporous laminate, pores connected with a winding path of regular or irregular shape including curved, curved linear and randomly oriented continuous pores, blocked connected pores or other porous webs investigation. In general, microporous laminates are defined by the pore size, the number of pores and the curvature of the microporous web, and the porosity is related to the size and number of pores. The pore size of a microporous laminate can be easily estimated by measuring the observed pore diameter at the surface of the material under electron microscope. Generally, materials can be included
455
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<img file="SE455918B_D0012.tif" />
to 95% pores and a pore size from 10 A to 100 µm are used to prepare a microporous laminate. The pore size and other parameters are characterized by the fact that the microporous structure can also be obtained by flow measurement, whereby the liquid flow J is obtained at a pressure difference Δ P through the laminate. The fluid flow through the laminate with even radius pores extending through the membrane and perpendicular to its surface with surface A is shown in Equation 13:
nTT<sup>4</sup> OP δη Ax (13) where J is the volume transported per unit time and the surface of the laminate containing N pieces of pore with radius r, η is the viscosity of the liquid and ZtP pressure difference through the laminate with thickness Δ x. For this type of laminate, the number of pores N can be calculated from Equation 14, where e represents the porosity defined as the ratio of empty volume to total volume of the laminate and A is the cross-sectional area of the laminate containing N pores.
N = ~ (14) no
The pore radius can be calculated from Equation 15:
Γ - Sn --y-<sup>T</sup>--- (15)
Δρ ε where J is the volume flow through the laminate per unit area produced by the pressure reference AP through the laminate, η and ε and Δ x have the above defined meaning and τ is the curvature defined as the ratio of the length of the diffusion path in the laminate to the thickness of the laminate. Equations of the above type are discussed in Transport Phenomena In Membranes by Lakshminatayanaiah, N., Chapter 6, 1969, Academic Press, Inc., New York.
As shown in p. 336 of this reference, in Table 6.13, the porosity of a laminate having pores with radius r can be expressed in relation to the size of the transported molecule with a radius a and when the ratio of molecular radius to pore
455 918 radius a / r decreases, the laminate becomes porous with respect to this molecule. Ie when the ratio a / r is less than 0.3, the laminate is substantially microporous expressed by the osmotic reflection coefficient σ, which decreases below 0.5. Microporous laminates having a reflection coefficient σ in the range of less than 1, usually from 0 to 0.5, and preferably less than 0.1 with respect to the active agent are suitable for the preparation of the system. The coefficient of reflection is determined by forming the material in the form of a laminate and conducting a water flow measurement as a function of the hydrostatic pressure difference and as a function of the osmotic pressure difference caused by the active agent. The osmotic pressure difference creates a hydrostatic volume flow and the reflection coefficient can be expressed by Equation 16:
<sub>σ</sub> osmotic volumetric flow hydrostatic volume flow '
The properties of microporous materials are described in Science, vol. 170, p. 1302 to 1305, (1970); Nature, vol. 214, p.
285 (1967); Polymer Engineering and Science, vol. 11, p. 284-288 (1971); U.S. Patent Nos. 3,576,809 and 3,575,536 and in Industrial Processing With Membranes by Lacey RE and Loeb, Sidney, p. 131 to 134 (1972) published by Wiley, Interscience, New York.
Microporous materials having a predetermined structure are commercially available and can be produced in a manner known per se. Microporous materials can be prepared by etching, nucleation, cooling a solution of a liquid polymer below the freezing point, the solvent evaporating from the solution in the form of crystals distributed in the polymer and then curing the polymer by removing the solvent crystals, by cold or heat stretching at low or high temperatures, until pores are formed, by leaching from the polymer a soluble component with a suitable solvent; by ion exchange reaction and by polyelectrolyte processes. Methods for making microporous materials are described in Synthetic Polymer Membranes by RE Resting, Chapters 4 and 5 (1971), Pub.
455 918 licensed by McGraw Hill, Inc.; Chemical Reviews, Ultrafiltration, vol. 18, p. 373 to 455 (1934); Polymer Eng. and Sci., vol. 11, No. 4, p. 284 to 288 (1971); J. Appl. Poly. Sci., Vol. 15, p. 811 to 829 (1971); and in U.S. Patents 3,556,259, 3,615,024, 3,751,536, 3,801,692, 3,852,224, and 3,849,528.
Microporous materials useful for preparing the laminate include microporous polycarbonates consisting of linear polyesters of carboxylic acid, in which the carbonate group reappears in the polymer chain, microporous materials prepared by phosphogenation of a dihydroxyl aromatic compound, such as bisphenol A, microporous poly (microporous poly) modacrylic copolymers comprising those formed from poly (vinyl chloride) 60% and acrylonitrile; styrene acrylic acid and its copolymers, porous polysulfones, characterized by diphenylene sulfone groups in a linear chain, halogenated poly (vinylidene), polychloroethers, acetal polymers, polyesters produced by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly (polyol saccharides), microporous poly (saccharides) with substituted and unsubstituted anhydroglucose units and preferably having a higher permeability for passage of water and biological fluids than semipermeable laminates, asymmetric porous polymers, cross-linked olefin polymers, hydrophobic or hydrophobic or hydrophobic or hydrophobic polymers, hydrophobic or hydrophobic U.S. Patent Nos. 3,597,752, 3,643,178, 3,654,066, 3,709,774, 3,718,532, 3 803 061, 3 852 224, 3 853 601 and 3 852 388 and in British Patent 1,126,849 and in Chem. Abst., Vol. 71 4274F, 22572F, 22573F (1969).
Additional microporous materials include poly (urethanes), cross-linked, chain-extended poly (urethanes), microporous poly (urethanes) in U.S. Patent 3,524,753, poly (imides), poly (benzimidazoles), collodion (cellulose nitrate with 11 X nitrogen), regenerated , semi-solid, cross-linked poly (vinylpyrrolidone), microporous materials prepared by diffusion of multivalent cations in polyelectrolyte sols as in U.S. Patent 4,55,918 to 3,556,259, anisotropic permeable microporous materials of ionically associated polyelectrolytes, porous polymers formed by co-precipitation of a polycation and a polyanion as described in U.S. Patents Nos. 3,276,589, 3,541,055, 3,541,066 and 3,546,142, derivatives of poly (styrene), such as poly (sodium styrene sulfonate) and poly (vinylbenzyl trimethyl armonium chloride), microporous materials disclosed in U.S. Patent Nos. 3,615,024, 3,646,178 and 3,852,224.
Further, the microporous molding material used for the purpose of the present invention includes embodiments in which the microporous laminate is formed in situ, by pore forming agents which are removed by dissolution or healing to form the microporous laminate during system operation. The pore former can be solid or liquid. The term liquid, according to the present invention, includes semi-solid and viscous liquids. The pore formers can be inorganic or organic. The pore formers suitable for the use of the invention include pore formers which can be extracted without any chemical change of the polymer. Pore-forming solids may have a grain size of about 0.1 to 200 µm and may include alkali metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate, sodium citrate, potassium nitrate and the like. Alkaline earth metal salts include calcium phosphate, calcium nitrate and the like. Transition metal salts include iron (III) chloride, iron (II) sulfate, zinc sulfate, copper (II) chloride, manganese fluoride, manganese fluorosilicate and the like. The pore formers include organic compounds such as polysaccharides. The polysaccharides include the sugars sucrose, glucose, fructose, mannitol, mannose, galactose, aldohexose, altarose, thalose, sorbitol, lactose, monosaccharides and disaccharides. Also organic aliphatic and aromatic oils and solids, including diols and polyols, exemplified by polyhydric alcohols, poly (alkylene glycols), polyglycols, alkylene glycols, poly (α-ω) alkylene diols, esters of alkylene glycols and the like, water-soluble cellulose polymers, hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, hydroxyethylcellulose and the like, water-soluble polymers such as polyvinylpyrrolidone, sodium
455 918 carboxymethyl cellulose and the like. The pore formers are non-toxic and upon removal, the laminate channels are formed in the laminate. In a preferred embodiment, the non-toxic pore-forming agents are selected from a group of inorganic and organic salts, carbohydrates, polyalkylene glycols, poly (α-ω) alkylene diols, esters of alkylene glycols, glycols and water-soluble cellulose polymers useful for forming microporous biological laminates. . General for. the object of the present invention, when the polymer constituting the laminate contains more than 25 weight-X pores, the polymer is a precursor to microporous laminates which upon removal of the pore former gives a laminate which is substantially microporous at concentrations lower than that at which the laminate behaves. as a semi-permeable laminate or membrane.
The term passage is used herein to denote a method for removing the agent or drug from the osmotic system. The term includes an aperture, nozzle, hole or bore through the semipermeable wall or laminated wall. The passage can be formed by mechanical drilling, laser drilling or by erosion with an erodible element, such as a gelatin plug in the use environment. A detailed description of osmotic passages and maximum and minimum dimensions for a passage is disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899.
The osmotically effective compounds which can be used for this purpose according to the present invention include inorganic and organic compounds which exhibit an osmotic pressure gradient through a semipermeable wall or through a semipermeable microporous laminated wall to outer liquid. The osmotically effective compounds (together with osmotically active polymers) suck liquid into the osmotic device and thereby make available in situ liquid for suction into an osmotically active polymer to facilitate its expansion, and / or form a solution or suspension containing a beneficial agents for delivery from the osmotic device. The osmotically effective compounds are also known as osmotically efficient soluble or osmotically active agents. They are osmotic
455 The 918 effective compounds are useful by mixing them with a beneficial agent and an osmotically active polymer to form a solution or suspension containing the beneficial agent which is osmotically delivered from the device. The term limited solubility in the present invention means agents having a solubility less than 5 wt. X in an aqueous liquid present in the environment. The osmotically soluble agents are used by homogeneous or heterogeneous mixing of the soluble agent with the agent or osmotically active polymer and then introducing them into the reservoir. The soluble agent and the osmotically active polymers attract liquid into the reservoir and provide a solution of the soluble agent in a gel which is delivered from the system while transporting undissolved and dissolved beneficial agents to the exterior of the system. Osmotically effective soluble agents useful for the prior purpose include magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium in sulfate, potassium hydrogen phosphate, potassium hydrogen phosphate, potassium hydrogen phosphate , sucrose, glucose, ad-lactose monohydrate and mixtures thereof. The amount of osmotically active agent in the room is usually from 0.01% to 30% or higher in the first composition and usually from 0.01% to 40% or higher in the second composition.
The osmotically soluble agent is initially present in excess and may be present in any physical form which is miscible with the beneficial agent and the osmotically active agent. The osmotic pressure of saturated solutions of various osmotically effective compounds and mixtures of compounds at 37 ° C in water is listed in Table 1. The table lists the osmotic pressure ir in atmospheres, ATM. The osmotic pressure is measured with a commercially available osmometer, which measures the vapor pressure difference between pure water and the solution to be analyzed and, according to standard thermodynamic principles, the vapor pressure ratio is converted to an osmotic pressure difference. Table 1 lists osmotic pressures from 20 ATMs to 500 ATMs, but of course, according to the invention, lower zero osmotic pressures and higher osmotic pressures than those listed in Table 1. The osmometer can be used.
455 918 used for the present measurements is a model 320B, sold by Hewlett Packard Co., Avonadale, Pennsylvania, USA.
<td></td><td>Table 1</td><td></td>
<td> □</td><td>Compound or mixture</td><td>Osmotic pressure ATM</td>
<td></td><td>Lactose-Fructose</td><td> 500</td>
<td></td><td>Dext praise - fr uk to s</td><td> 450</td>
<td> 10</td><td>Sucrose-Fructose</td><td> 430</td>
<td></td><td>Mannitol-Fructose</td><td> 415</td>
<td></td><td>Sodium chloride</td><td> 356</td>
<td></td><td>Fructose</td><td> 355</td>
<td></td><td>Lactose-Sucrose</td><td> 250</td>
<td> 15</td><td>potassium chloride</td><td> 245</td>
<td></td><td>Lactose-Dextrose</td><td> 225</td>
<td></td><td>Mannitol-Dextrose</td><td> 225</td>
<td></td><td>Dextrose-Sucrose</td><td> 190</td>
<td></td><td>Mannitol-sucrose</td><td> 170</td>
<td> 20</td><td>dextrose •</td><td> 82</td>
<td></td><td>potassium sulphate</td><td> 39</td>
<td></td><td>mannitol</td><td> 38</td>
<td></td><td>Sodium phosphate, tribasic, 12 ^ 0</td><td> 36</td>
<td></td><td>Sodium phosphate, dibasic, 7 ^ 0</td><td> 31</td>
<td> 25</td><td>Sodium phosphate, dibasic, 12H £ 0</td><td> 31</td>
<td></td><td>Sodium phosphate, dibasic, anhydrous</td><td> 29</td>
<td></td><td>Sodium phosphate, monobasic,</td><td> 28</td>
The osmotically active polymers which are suitable for forming the first osmotic composition and also suitable for forming the second osmotic composition are osmotically active polymers which exhibit liquid suction properties. The osmotically active polymers can swell, hydrophilic polymers which interact with water and aqueous biological fluids to swell or expand to an equilibrium state. The osmotically active polymers exhibit an ability to swell in water and retain a significant portion of the absorbed water in the polymer structure. The osmotically active polymers swell or expand to a very high degree, '23
455 918 usually · exhibiting 2 to 50 times volume increase. The swellable hydrophilic polymers are, according to a presently preferred embodiment, easily cross-linked, such as cross-links formed by covalent or ionic bands. The osmotically active polymers may come from the plant kingdom, the animal kingdom or be of synthetic origin. The osmotically active polymers are hydrophilic polymers. Hydrophilic polymers suitable for the present purposes include poly (hydroxyalkyl methacrylate) having a molecular weight of 30,000 to 5,000,000, poly (vinylpyrrolidone) having a molecular weight of 10,000 to 360,000, anionic and cationic hydrogels, polyelectrolyte complex, poly (vinyl alcohol) having a low acetate residue, cross-linked with glyoxal, formaldehyde or glutaraldehyde and with a degree of polymerization from 200 to 30,000, a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose, a water-insoluble, water-swellable copolymer formed by dispersion of finely divided copolymers of maleic anhydride with styrene, ethylene, propylene, butene or isobutene, crosslinked with from 0.001 to about 0.5 moles of polyunsaturated crosslinking agent per mole of maleic anhydride in the copolymer, water swellable polymers of N-vinyllact.
Other osmotically active polymers include polymers that form hydrogels such as Carbopol <9, acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000, Cyanams (J9 polyacrylamides, crosslinked water-swellable indene maleic anhydride polymers, Goodrite® polyacrylic acid from 000,000 200,000, Polyox® polyethylene oxide polymers having a molecular weight of 100,000 to 5,000,000, starch graft copolymers, Aqua-Keeps® acrylate polymers, diester crosslinked polyglucan and the like. Representative polymers forming hydrogels are known in the prior art by U.S. Patent Nos. 3,865,108, 4,002,173, and 4,207,893, and in the Handbook of Common Polymers by Scott and Roff, published by the Chemical Rubber Company, Cleveland, Ohio, USA. The amount of osmotically active polymer in the first osmotic composition is about 0.01 to 90x and the amount of osmotically active polymer in the second osmotic composition is 15 to 95x. In a presently preferred embodiment, the molecular weight of the osmotically active polymer in the second osmotic composition is larger than molecule
455 918 weight of the osmotically active polymer in the first osmotic composition.
The liquid suction in the osmotically active polymer can be done by a procedure described below. A 1.3 cm diameter round bowl, fitted with a 1.3 cm stainless steel plug is fed with a known amount of polymer with the plug extending at either end. The plug and nozzle are placed in a Carver press with plates between 94 and 150 ° C. A pressure of 68 to 103 MPa is applied to the plugs. After 10 to 20 minutes of heat and pressure, the electric heating of the plates is turned off and water mains water is allowed to circulate through the plates. The resulting 1.3 cm diameter slab is placed in an air suspension coating loaded with 1.8 kg of saccharide cores and coated with cellulose acetate having an acetyl content of 39.8% dissolved in 94: 6 by weight Cf OH to obtain a solution of 3% by weight. The coated system is dried overnight at 50 ° C. The coated disks are immersed in water at 37 ° C and removed periodically for gravimetric determination of suction water. The initial suction pressure was calculated using the water transmission constant of cellulose acetate following normal suction values of the membrane surface and thickness. The polymer used in this determination was the sodium derivative of Carbopol-934 polymer prepared according to the procedure described in BF Goodrich
Service Bulletin GC-36, CarbopolC ^ Water-Soluble Resins, p. 5, published by BF Goodrich, Ekron, Ohio, USA.
The cumulative weight gain values y as a function of time t of the water-soluble polymeric disk coated with cellulose acetate 2 were used to determine the equation y = c + bt + at passed through these points by the least squares method.
The weight gain for Na Carbopol-934 is indicated by Equation 17, where the weight gain equals 0.359 + 0.665t - 0.00106t, where t is included in the magnitude of ninety. The water flow per unit of time is at each point equal to the slope of the line, which is given by the following equations 18 and 19:
455 918 dy _ d (0.359 + 0.665t - 0.00106t<sup>2</sup>dt ~ dt dy _ 0.665 - 0.00212t dt (18) (19)
To determine the initial flow per unit of time is estimated
<img file="SE455918B_D0013.tif" />
is normalized to the coefficient b. Normalization of the suction amount per unit time, the membrane surface area and the thickness and the membrane permeability constant against water, K, then allows π to be determined according to Equation 20:
<img file="SE455918B_D0014.tif" />
-4 2 with K = 1.13 x 10 cm / h. The value (π) of NaCl was determined by +
a Hewlett-Packard vapor pressure osmometer to 345 atm - 10% and the K value of cellulose acetate used in this experiment calculated for the NaCl suction value was determined at 1.9 x 10 cm / h atm.
Substitution of these values in the calculated Kn expression (1.9 x 10<sup>-7</sup>/ cm<sup>2</sup>/h.atm) (tt) = 1.13 x 10<sup>-</sup>^ cm<sup>2</sup>/ h gives π = 600 atm at t = 0. As a method of determining the efficiency of a polymer with respect to the duration of zero-order driving force, percent water uptake before the water flow values is reduced to 90% of their original value. The value of the slope according to the equation on a straight line based on the increase in weight * from the axis is equal to the initial value of dy / dt developed at t = 0, with the intersection of y, c defining the linear swell time with (dy / dt) 0 = 0.665 and the y intersection of 0, giving y = 0.665t + 0.359. To determine when the value of the cumulative water uptake is 90% below the initial uptake, the following expression for tq<sup>A</sup>± 2 + bt + c _ ΔW 'bt + cw (21)
-0.00106 t<sup>2</sup> + 0.665 t + 0.359
0.665t + 0.359
455 918 solution for t
-0,00106t<sup>I 2</sup> + 0.0665t + 0.0359 = 0. <sub>0</sub> 1/2 (23)
-0,0665 - /”(0,0665)<sup>z</sup> - 4(-0,00106) (0,0359)_7 <sup>h =</sup> 2 (-0.00106) with t - 62 min. and the weight gain is -0.00106 (62) + (0.665) (62) + 0.359 = 38 µl with the original sample weight = 100 mg, thus (yew / w) 0.9 x 100 = 38%. The results are shown in Figure 8 for a graphical representation of the values. Other methods available to study the interface of the hydrogel solution include rheological analysis, viscometric analysis, ellipsometry, contact angle measurements, electrokinetic determinations, infrared spectrography, optical microscopy, interface morphology and microscopic examination of a working device.
The term active agent used in the present specification includes any beneficial agent or compound which can be delivered from the device to give a beneficial and beneficial effect. The agent can be insoluble to very soluble in the surrounding liquid which enters the device and can be mixed with an osmotically active compound and an osmotically active polymer. The active agent includes pesticides, herbicides, germicides, biocides, algicides. rodenticides, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, disinfectants, sterilizers, catalysts, chemical reactants, fermentation agents, fertility agents, fertility drugs, sexual sterilizers, fertility agents, sexual sterilizers, sexual sterilizers, fertility agents , which is beneficial to the environment of use.
In the specification and the accompanying drawings, the term beneficial agent includes drugs and the term drug includes any physiologically or pharmacologically active substance which provides a local or systemic efficacy to animals including warm-blooded mammals, humans and primates, poultry, reptiles and zoos. The term physiological is used here to
455 918 denote administration of a drug to provide normal levels and functions. The term pharmacological denotes various variations in the response to the amount of drug administered to the host. See Stedman's Medical Dictionary, 1966, published by Williams and Wilkins, Baltimore, Maryland, USA. The term drug preparation is used herein to denote drugs in the room mixed with an osmotically active soluble agent and / or an osmotically active polymer and, if applicable, with a binder and lubricant. The active drug which can be released includes inorganic and organic compounds without restriction, including drugs acting on the peripheral nervous system, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscle, blood circulatory system, endocrine system, synoptic punctures, synoptic points, immunological systems, organ systems, the reproductive system, the skeletal system, the active drug can be delivered to act on these animal systems including sedatives, hypnotic agents, psychotic agents, sedatives, anticonvulsants, muscle relaxants, muscle relaxants, analgesics, anti-inflammatory agents, local anesthetics, muscle contracting agents, antimicrobials, antimalarials, hormonal agents, contraceptives, sympathomimetics, diuretics, antiparasitic agents, neoplastic agents, hypoglycemic agents, ophthalmic agents, electrolytes, diagnostic agents and cardiovascular drugs.
Exemplary drugs that are very soluble in water and can be delivered from devices of the present invention comprises proklorperazinedisylat, iron (II) sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, bensfetaminhydroklorid, isoproternolsulfat, methamphetamine hydrochloride, phenmetrazine hydrochloride, betankolklorid, metacholinklorid, pilocarpine hydrochloride, atropine sulphate, metascopolamine bride, isopropamide iodide, tridihexetyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, metoprolol tartrate, cimetidine hydrochloride, theophylline 455,918 cholinate, cephalexin hydrochloride and the like.
Examples of drugs which have poor solubility in water and which can be dispensed with the devices of the present invention include diphenidol, mexylphine hydrochloride, proclorperazine maleate, phenoxybenzamine, thietylperazine maleate, anisindone, diphenadione etherityl tetranitrate, dizoxin, dizoxin. chloromadinone acetate, phenaglycodole, allopurinol, aluminum acetyl salicylate, methotrexate, acetylsulfisoxazole, erythromycin, progestin, estrogen progestational, corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, triamcinolone, methyltesterone, 178-estradiol, ethinylestradiol, prazosin hydrochloride ethinyl estradone, noretone, 19 and similar.
Examples of other drugs that may be delivered by the osmotic device include acetylsalicylic acid, indomethacin, naproxen, phenoprofen, sulidac, diclofenac, indoprofen, nitroglycerin, propranolol, metoprolol, valproate, oxprenolol, timololin, cenolidine, atenolol, atenolol, , chlorpromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, pivaloyloxyethyl, esters of α-methyldopahydrochloride, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, proszin, haloperidol, zomepirac, iron (II) lactate, wine fireplace, diazepam, phenoxybenzamine, α-blocking agents, calcium channel blocking drugs such as nifedipine, diliazene, verapamil, beta blockers and the like. Charitable drugs are known from e.g. Pharmaceutical Sciences, compiled by Remington, 14th Edition, (1979), published by Mack Publishing Co., Easton, Pennsylvania, USA; The Drug, The Nurse, The Patient, Including Current Drug Handbook, (1974-1976) by Falconer and co-workers, published by Saunder Company, Philadelphia, Pennsylvania, USA and Medical
Chemistry, 3rd edition, vol. 1 and 2 by Burger, published by Wiley-Interscience, New York, USA.
The drug, may exist in various forms, such as unchanged molecules, molecular complexes, pharmacologically acceptable salts, such as
455 918 hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and salicylate. For example, for acidic drugs, salts of metals, amines and organic cations, quaternary ammonium can be used. Derivatives of drugs such as esters, ethers and amides can be used. A drug which is water-insoluble may also be used in the form of a water-soluble derivative thereof to serve as a soluble agent and upon release from the device is converted by enzymes hydrolyzed at the body's pH or other metabolic process10 to the original biologically active form.
The agent comprising the drug may be present in the room with a binder, dispersant, wetting agent, suspending agent, lubricant and dye. Representative among these include suspending agents such as acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, colloidal silica, hydroxyethyl cellulose, pectin, gelatin and calcium silicate, magnesium silicate, binder such as polyvinyl pyridine, binder such as polyvinyl pyridine fatty acid and the like. The term drug preparation comprises the drug being present in the room together with an osmotically active agent, an osmotically active polymer, a binder and the like. The amount of beneficial agent in the device usually ranges from 0.05 ng to 5 g or more, with the individual device containing, for example, 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g and similar. The devices may be administered once, twice or three times daily.
The solubility of the beneficial agent in the liquid can be determined in known manner. One method consists in preparing a saturated solution consisting of the liquid plus the agent which is determined by analyzing the amount of agent present in a specified amount of the liquid. A simple apparatus for this purpose consists of a medium-size test tube upright fixed in a water bath at constant temperature and pressure, in which the liquid and agent are placed under agitation with a rotating glass coil. After a given stirring time, a certain amount of the liquid is analyzed and stirred continuously for a further set of time. If the assay shows no increase in the dissolved agent consecutively
455 918 stirring periods, in the presence of excess solid insoluble in the liquid, the solution is saturated and the result is considered the solubility of the product in the liquid. If the agent is soluble, an osmotically effective compound may not need to be added. Many other other methods are available for determining the solubility of an agent in a liquid. Typical methods useful for measuring solubility are chemical and electrical conductivity. Details of various methods for determining solubility are described in United States Public Health Service Bulletin, No. 67, of the Hygenic Laboratory; Encyclopedia of Science and Technology, vol. 12, p. 542 to 556 (1971), published by McGraw-Hill, Inc. and Encyclopedia Dictionary of Physics, vol. 6, p. 547 to 557 (1962), published by Pergamon Press, Inc.
The osmotic device according to the invention is produced by standard technique. In one embodiment, for example, the beneficial agent is mixed with an osmotically active agent and an osmotically active polymer and pressed into a solid piece of dimensions corresponding to the internal dimensions of the space adjacent the passage or the beneficial agent is mixed. and other formulation-forming ingredients and a solid or semi-solid solvent by conventional means ball mill milling, calendering, stirring or rolling milling and then pressed into a predetermined form. Then, a layer of a composition consisting of an osmotically active agent and an osmotically active polymer is placed in contact with the layer containing beneficial agent and the two layers are surrounded by a semi-permeable wall. The layer of beneficial agent composition and osmotically active agent and osmotically active polymer can be provided by a conventional two-layer tablet press technique. The wall can be applied by casting, spraying or dipping the pressed mold pieces into a wall forming material. Another and currently preferred technique that can be used for application of the wall is the air suspension coating process. This method consists in suspending and tumbling the pressed compositions in an air stream and a wall-forming composition until the wall surrounds and coating the two pressed compositions.
455 918
The process is repeated with another laminate forming composition to form a laminated wall. The air suspension process is described in US Patent 2,799,241; J. Am. Pharm. Assoc., Vol. 48, p. 451 to 459 (1979) and ibid, vol. 49, p. 82 to 84 (1960). Other standard manufacturing procedures are described in Modern Plastics Encyclopedia, vol. 46, p. 62 to 70 (1969) and in Pharmaceutical Sciences of Remington, 14th Edition, p. 1626 to 1678 (1970), published by Mack Publishing Co., Easton, Pennsylvania, USA.
Examples of solvents suitable for preparing laminates include inert inorganic and organic solvents which do not seriously affect the materials and the final laminated wall. The solvents generally include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic solvents, heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, kloroformnitroetan , nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphthalene, 1,4-dioxane, tetrahydrofuran, diglyme, water and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol and ethylene dichloride and methanol.
Detailed description of examples
The following examples illustrate the invention and are not to be construed as limiting the scope of the invention in any way, since these examples and other equivalents thereof will be apparent to those skilled in the art in light of the present disclosure, figures and appended claims.
455 918
Example 1
An osmotic delivery device was prepared as an osmotic tablet of shape and size adapted for oral administration to the gastrointestinal tract as follows: mesh, after which 100 g of nifedipine was passed through the sieve with the sieve number 40 mesh
25 g of hydroxypropylmethyl cellulose was passed through the sieve of 40 mesh and finally 10 g of potassium chloride was passed through the sieve of 40 mesh. Then all the sieved ingredients were added to the vessel in a laboratory mixer and the ingredients were mixed for 15-20 minutes to obtain a homogeneous mixture. Then, a granulation liquid consisting of 250 ml of ethanol and 250 ml of isopropyl alcohol was prepared and the granulating liquid was added to the mixing vessel, first 50 ml which was injected into the container under constant mixing, then 350 ml of granulating liquid was slowly added to the container, then the moist mass was further mixed. to 20 minutes. Then, the moist granules were passed through a screen with 16 mesh screen and dried at room temperature for 24 hours, after which the dry granules were passed through a screen with 16 mesh screen. Then, 10 g of magnesium stearate was added to the dry granules and the ingredients were rolled for 20-30 minutes on a standard two-roll mill.
Then a second osmotic composition was prepared as follows: first, 170 g of polyethylene oxide having a molecular weight of
000 000 pass a sieve of 40 mesh sieve, after which 72.5 g of sodium chloride was passed through the sieve of 40 mesh sieve and the ingredients were added to a mixing container and mixed for 10-15 minutes. Then, a granulation liquid was prepared by mixing 350 ml of methanol and 150 ml of isopropyl alcohol, after which the granulation liquid was added to the mixing vessel in two steps. First, 50 ml of granulating liquid was injected into the container under constant mixing and then 350 ml was slowly added to the container and the moist mixture
455 The mixture was mixed for 15-20 minutes to a homogeneous mixture. Then, the wet mixture was passed through a screen of 16 mesh screen, spread on a stainless steel tray and dried at room temperature at 22.5 ° C for 24 hours. The dried mixture was passed through a sieve of 16 mesh screen, after which it was milled with 5 g of magnesium stearate on a two-roll mill for 20-30 minutes.
A number of drug cores were prepared by pressing the two compositions onto a Manesty Layer press. The drug containing the composition was fed into the mold hole in the press and pressed into a solid layer. Then, the second osmotic composition was introduced into the cavity over the compressed layer and pressed into a solid layer to form a two-layer drug core.
The drug cores are then coated with a semipermeable wall-forming composition consisting of 95 g of cellulose acetate having an acetyl content of 39.8% and 5 g of polyethylene glycol 4000 in a solvent consisting of 1960 ml of methylene chloride and 820 ml of methanol. The drug cores are coated with the composition forming a semipermeable wall until the wall surrounds the drug core. A Wurster air suspension coating was used to form the semi-permeable wall. The coated cores are then spread on a tray and the solvent is evaporated in a circulating air oven at 50 ° C for 65 hours. After cooling to room temperature, a 0.26 mm diameter passage was recorded by laser drilling into the semipermeable wall connecting the exterior of the osmotic device to the composition containing the drug. The osmotic device weighed 262 mg and contained 30 mg of drug in the first composition weighing 150 mg, the second composition weighing 75 mg and the semipermeable wall weighing 37 mg. The first osmotic composition of the osmotic device consists of 30 mg of nifedipine, 106 mg of polyethylene oxide, 3 mg of potassium chloride, 7.5 mg of hydroxypropylmethylcellulose and 3 mg of magnesium stearate. The second osmotic composition consisted of 51 mg of polyethylene oxide, 22 mg of sodium chloride and 1.5 mg of magnesium stearate. The device had a diameter of 8 mm, a surface of 1.8 cm and it
455 The 918 semipermeable wall was 0.17 mm thick. The cumulative amount of drug released from the device is shown in Figure 9.
Example 1A
Osmotic delivery systems were prepared with a first composition containing 25 to 100 mg of nifedipine, 100 to 325 mg of polyethylene oxide with a molecular weight of 200,000, 2 to 10 mg of potassium chloride, 5 to 30 mg of hydroxypropylmethyl cellulose and 2 to 10 mg of magnesium stearate and a second composition to 175 mg of polyethylene oxide having a molecular weight of 5,000,000, 20 to 75 mg of sodium chloride and 1 to 5 mg of magnesium stearate. The procedure of Example 1 was repeated to prepare osmotic devices of the following compositions: (a) an osmotic device with a first composition containing 60 mg of nifedipine, 212 mg of polyethylene oxide, 6 mg of potassium chloride, 15 mg of hydroxypropylmethylcellulose and 6 mg of magnesium stearate; and a second composition comprising 102 mg of polyethylene oxide, 44 mg of sodium chloride and 3 mg of magnesium stearate; and (b) an osmotic device having a first composition comprising 90 mg of nifedipine, 318 mg of polyethylene oxide, 9 mg of potassium chloride, 22.5 mg of hydroxypropylmethylcellulose and 9 mg of magnesium stearate, and a second composition of 102 mg of polyethylene oxide, 66 mg of sodium chloride and 4 mg. , 5 mg magnesium stearate. In one embodiment, the osmotic device described in (a) and (b) consists of an initiator coating on the outer semipermeable wall. The initiator coating consists of 30 mg of nifedipine and hydroxypropylmethyl cellulose. In operation in a liquid use environment, the initiator coating provides immediate drug available for direct therapy.
Example 2
The procedure of Example 1 was repeated with all conditions previously described except that the drug in the room was replaced by a number selected from a group consisting of beta blockers, anti-inflammatory, analgesic, sympathomimetic, antiparkinsonian or diuretic drugs.
455 918
Example 3
An osmotic therapeutic device for controlled and continuous oral release of the beneficial calcium channel blocking drug verapamil was prepared as follows: 90 mg of verapamil, 50 mg of sodium carboxyvinyl polymer with a molecular weight of 200,000 sold under the trade name Carbopol® S 'polymer, 3 mg of sodium chloride, 7.5 mg of hydroxypropylmethyl cellulose and 3 mg of magnesium stearate were mixed thoroughly in the manner described in Example 1, and pressed into a Manesty press with a 0.8 cm punch using a 1 1/2 ton printing head to prepare a layer of the drug composition. Then 51 mg single-molecular weight carboxyvinyl polymer of 3,000,000 and sold under the trade name CarbopolV> polymer, 22 mg sodium chloride and 2 mg magnesium stearate were thoroughly mixed and added to the Manesty press and pressed to form a layer of expandable omotic composition in contact with the layer osmotic drug composition.
Then, a semipermeable wall through mixture of 170 g of cellulose acetate with a 39.8% acetyl content was formed with 900 ml of methylene chloride and 400 ml of methanol and the two-layered compartment was extruded to form a body with an air suspension machine until a 130 µm thick semipermeable wall . The coated device was dried for 72 hours at 50 ° C and then a 0.2 mm diameter passage was laser drilled through the semipermeable wall to connect the drug-containing layer to the exterior of the drug release device for an extended period of time.
Example 4
The procedure of Example 3 was repeated under all conditions described there except that the drug in the osmotic device was fendiline, diazoxide, prenylamine or diltiazene.
455 918
Example 5
An osmotic therapeutic device for delivering the drug sodium diclofenac for use as an anti-inflammatory agent was prepared by first pressing, in a Manesty press, an osmotic drug composition containing 75 mg sodium diclofenac, 300 mg sorbitol, 30 mg sodium bicarbonate, 26 mg pectin acid, 10 mg pectin and pressing the composition into a cavity for a solid layer. Subsequently, the cavity was fed with a second and larger force generating composition containing 122 mg of pectin with a molecular weight of 90,000 to 130,000, 32 mg of mannitol, 20 mg of polyvinylpyrrolidone and 2 mg of magnestium stearate and pressed to form a second layer in close contact with the first layer. The second layer had a density of 1.28 g / cm 2 and a hardness number greater than 12 kg. Subsequently, the two-layer core was surrounded with a semipermeable wall consisting of 85 g of cellulose acetate with an acetyl content of 39.8% and 15 g of polyethylene glycol 4000, forming a solution containing 3 wt.% Fc wall-forming composition consisting of 1960 ml of methylene chloride and 819 ml of methanol. The coated device was dried for 72 hours at 50 ° C and then laser penetrated a 0.26 mm diameter passage through the wall. The semipermeable wall was 0.1 mm thick and the device had a surface area of 3.3 cm, and had an average released amount of drug of 5.6 mg per hour over a 12 hour period. The cumulative amount released is illustrated in Figure 10. A small vertical line represents the minimum and maximum drug release from five measured systems at this time.
Example 5A
The procedure of Example 5 was followed to obtain an osmotic device where the compartment contained a mixture of osmotically active polymers. The compartment contained a first composition weighing 312 mg and consisting of 48% sodium diclofenac drug, 38% polyethylene oxide - osmotically active polymer having a molecular weight of 200,000, 10% polyethylene glycol osmotic active polymer having a molecular weight of 20,000, 2% sodium chloride and 2 % magnesium stearate and a second composition weighing 150 mg and
455 918 consisting of 93% polyethylene oxide having a molecular weight of 5,000,000,% sodium chloride and 2 x magnesium stearate.
Example 6
In this example, the increase in osmotic pressure is made for a number of compositions consisting of an osmotically active agent and osmotically active polymer to demonstrate the advantages of using the present invention. The measurements were made by measuring the amount of suction through the semipermeable wall of a bag containing an osmotically active agent or an osmotically active polymer or a composition consisting of an osmotically active agent and an osmotically active polymer. The semipermeable wall of the bag was formed by a cellulose acetic acid 39.8%. The measurements were made by weighing the dry ingredients in the semipermeable bag, followed by weighing the empty semipermeable bag after holding the bag in a water bath at 37 ° C for various periods of time. The increase in weight is due to the water intake through the semipermeable wall caused by the osmotic pressure gradient through the wall. The osmotic pressure curves are illustrated in FIG. 11. In FIG. 11 the curved line of triangles denotes the osmotic pressure of polyethylene oxide having a molecular weight of 5,000,000, the curved line of circles denotes the osmotic pressure of a composition containing polyethylene oxide having a molecular weight of 5,000,000 and sodium chloride with the ingredients present in the composition 9.5 parts by weight of osmotically active polymer to 0.5 parts by weight of osmotically active agent, the curved line of squares denotes a composition consisting of the same osmotically active polymer and osmotically active agent in a ratio of 9 parts of osmotically active polymer to some osmotically active agent, the curved line of hexagons denotes the same composition consisting of the osmotically active polymer and the osmotically active polymer. the active agent in the ratio of 8 parts to 2 parts and the dashed lines denote the osmotically active agent sodium chloride. The mathematical calculations used for the formula dw / dt = A (KAir) / h, where dw / dt is the amount of water sucked in the mean time, A denotes the surface of the semipermeable wall and the K permeability coefficient
455 918 t. Also in Fig. 11, the amount of suction water, V V / W ^, is derived from the weight of the osmotically active polymer plus the osmotically active agent.
Example 7
An osmotic therapeutic device for delivering sodium diclofenac was prepared by sieving a composition containing 49 X sodium diclofenac, 44 X polyethylene oxide having a molecular weight 10 of 100,000, 2 X sodium chloride, and 3 X hydroxypropyl methyl cellulose through a sieve screened with the sieve of the 40 mesh screen. with an alcohol solvent used in the ratio of 75 ml of solvent to 100% granulation.
The wet granulate was sieved through a sieve of 16 mesh sieve, dried at room temperature for 48 hours in vacuo, passed through a sieve of 16 mesh sieve, and mixed with 2X magnesium stearate which passed a sieve of 80 mesh sieve. The composition was pressed in the manner described above.
Then, a composition containing 73.9 X pectin having a molecular weight of 90,000 to 130,000, 5.8 X microcrystalline cellulose, 5.8 X polyvinylpyrrolidone, 14.3 X sodium chloride and 2 X sucrose were passed through a 40 mesh sieve. , mixed with an organic solvent in the ratio of 100 ml of solvent to 100 g granulation mass for less than 25 minutes, allowed to pass through a sieve of 16 mesh screen, dried for 48 hours at room temperature under vacuum, was again passed through a screen of 16 mesh sieve, mixed with 2 X magnesium stearate and then pressed into layers described in the above paragraph.
The double-layered drug core is coated by dipping with a wall-forming composition consisting of 80 X cellulose acetate having an acetyl content of 39.8 X, 10 X polyethylene glycol 4000 and 10 X hydroxypropyl methyl cellulose. A passage was drilled through the wall communicating with the drug-containing composition.
The diameter of the passage was 0.38 mm. The theoretical cumulative release profile of the device is shown in Figure 12. Figure 13 shows the theoretical release rate in mg per hour for the osmotic device.
455 918
Example 8
The procedure of Example 7 was repeated under all conditions as described except that the osmotically active polymer in the drug composition was polyoxyethylene polyoxypropylene copolymer in mass having a molecular weight of about 12,500.
Example 9
An osmotic device was prepared according to the above procedures. The device of this example consisted of a single composition containing 50% sodium diclofenac, 46% polyethylene oxide having a molecular weight of 100,000, 2% sodium chloride and 2% magnesium stearate. The device had a semipermeable wall consisting of 90% cellulose acetate with 39.8% acetyl and 10% polyethylene glycol 4000. The cumulative amount released from this device of a single composition is 40% of the device of two compositions. The cumulative amount released is illustrated in Figure 14.
Example 10
The cumulative average amount released in vivo and in vitro of diclofenac sodium from an osmotic device comprises a first osmotic composition consisting of 75 mg of diclofenac sodium, 67 mg of polyethylene oxide having a molecular weight of 100,000, 3.0 mg of sodium chloride, 4.5 mg of hydroxypropylmethylcellulose, 0 mg of magnesium stearate, a second osmotic composition remote from the release passage, consists of 51 mg of polyethylene oxide having a molecular weight of 5,000,000, 22.5 mg of sodium chloride and 1.5 mg of magnesium stearate and surrounded by a semi-permeable wall consisting of 90% cellulose acetate with an acetyl content of 39.8% and 10% polyethylene glycol 4000 were measured in vivo and in vitro on laboratory dogs. The amount of drug released at various times in vivo was determined by administering a number of devices to the animals and measuring the amount released from the corresponding device at the appropriate residence time. The results are shown in FIG. 15, where circles with rods show in vitro average cumulative release and triangles with rods show in vivo average
455 918 cumulative release.
The average in vivo and in vitro cumulative release of the nifedipine-containing device was measured as described immediately above. The osmotic device consisted of a composition adjacent to the passage consisting of 30 mg of nifedipine, 106.5 mg of polyethylene oxide having a molecular weight of 200,000, 3 mg of potassium chloride, 7.5 mg of hydroxypropylmethylcellulose and 3 mg of magnesium stearate; a composition at a distance from the passage consisting of
52 of polyethylene oxide having a molecular weight of 5,000,000, 22 mg of sodium chloride and 1.5 mg of magnesium stearate, and a semipermeable wall consisting of 95% cellulose acetate having a 39.8% acetyl content and 5% hydroxypropyl methyl cellulose. Fig. 16 shows the release from the system. In Figure 16, the circles in vivo represent cumulative release and the in vitro triangles represent average cumulative release.
Example 11
The procedure of Example 10 was followed to prepare an osmotic therapeutic delivery system consisting of a first or drug composition weighing 638 mg and consisting of 96% cephalexin hydrochloride, 2% Povidone (polyvinylpyrrolidone) and 2% magnesium stearate and a second or osmotic driving composition weighing
200 mg and consisting of 68.5% polyethylene oxide having a molecular weight of 5 x 10 5, 29.5% sodium chloride and 2% magnesium stearate; a semipermeable wall weighing 55.8 mg consisting of 80% cellulose acetate with an acetyl content of 39.8%, 14% polyethylene glycol 4000 and 14% hydroxypropylmethyl cellulose and an osmotic nozzle having a diameter of 0.039 mm. The device had an average release rate of about 54 mg per hour over a period of 9 hours.
The new osmotic system of the present invention uses dual means to provide an exact amount of drug release which is difficult to deliver in the use environment while maintaining the integrity and type of the system. Although described and pointed out embodiments and advantages of the invention relate to presently preferred embodiments,
455 918 those skilled in the art of dispensing will recognize that various modifications, modifications, additions and exclusions in the illuminated systems and described systems can be made without departing from the spirit of the invention.
455 918
Contents3
21 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4 Sheet 5 Sheet 6 Sheet 7 Sheet 8 Sheet 9 Sheet 10 Sheet 11 Sheet 12 Sheet 13 Sheet 14 Sheet 15 Sheet 16 Sheet 17 Sheet 18 Sheet 19 Sheet 20 Sheet 21
51 members in 21 offices
Priority claims4
| Document | Office | Kind | Date |
|---|---|---|---|
| 49376083 | United States of America | A | |
| 49376083 | United States of America | A | |
| 493760 | – | – | – |
| US19830493760 | – | – | – |
Members51
| Document | Office | Kind | |
|---|---|---|---|
| GB8334189D0 | United Kingdom | D0 | |
| DK99784D0 | Denmark | D0 | |
| IT8467283D0 | Italy | D0 | |
| SE8402512D0 | Sweden | D0 | |
| BE898819A | Belgium | A | |
| IL71727A0 | Israel | A0 | |
| IL71727D0 | Israel | D0 | |
| IE840010L | Ireland | L | |
| DK99784A | Denmark | A | |
| NO840248L | Norway | L | |
| SE8402512L | Sweden | L | |
| AU2251183A | Australia | A | |
| DE3417113A1 | Germany | A1 | |
| FR2545721A1 | France | A1 | |
| ZA842422B | South Africa | B | |
| NL8401470A | Netherlands (Kingdom of the) | A | |
| GB2140687A | United Kingdom | A | |
| BE900817R | Belgium | R | |
| ES532018A0 | Spain | A0 | |
| ES8503503A1 | Spain | A1 | |
| JPS6041609A | Japan | A | |
| IT8467283A1 | Italy | A1 | |
| US4612008A | United States of America | A | |
| NZ206600A | New Zealand | A | |
| GB2140687B | United Kingdom | B | |
| CA1222950A | Canada | A | |
| IT1178911B | Italy | B | |
| IT8467283A0 | Italy | A0 | |
| AU566110B2 | Australia | B2 | |
| FR2545721B1 | France | B1 | |
| SE455918BThis record | Sweden | B | |
| US4765989A | United States of America | A | |
| US4783337A | United States of America | A | |
| IL71727A | Israel | A | |
| DE3417113C2 | Germany | C2 | |
| CH669329A5 | Switzerland | A5 | |
| IE56515B1 | Ireland | B1 | |
| ATA150789A | Austria | A | |
| US5082668A | United States of America | A | |
| DK163910B | Denmark | B | |
| MX163518B | Mexico | B | |
| AT394944B | Austria | B | |
| MX9203733A | Mexico | A | |
| NO170834B | Norway | B | |
| DK163910C | Denmark | C | |
| NO170834C | Norway | C | |
| ATA88084A | Austria | A | |
| JPH0575725B2 | Japan | B2 | |
| AT397180B | Austria | B | |
| NL192250B | Netherlands (Kingdom of the) | B | |
| NL192250C | Netherlands (Kingdom of the) | C |
2 legal events, as the office reported them to INPADOC
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Numbers
- Publication, DOCDB
- 455918
- Publication, EPODOC
- SE455918
- Application
- 8402512
- Application, DOCDB
- 8402512
- Application, EPODOC
- SE19840002512
Titles2
- Swedish
- OSMOTISK AVGIVNINGSANORDNING MED DUBBEL TERMODYNAMISK VERKAN
- English
- OSMOTIC DELIVERY DEVICE WITH DOUBLE THERMODYNAMIC EFFECT
Classification
- CPC, 1
- A61K9/0004
- IPC, 5
- A61K9 00
- A61K9 44
- A61K9 52
- A61M31 00
- C07D501 22
