CA1189754A - Simultaneous delivery of two drugs from unit delivery device - Google Patents

Abstract

ABSTRACT
An osmotic device is disclosed for delivering two beneficial drugs to an environment of use. The device comprises a wall surrounding a lumen divided into a first compartment containing a drug that is separated by a hydrogel partition from a second compartment containing a different drug. An orifice through the wall communicates with the first compartment for delivering drug formulation from the first compartment, and another orifice through the wall communicates with the second compartment for delivering drug formulation from the second compartment. In operation, drug formulation is dispensed separately from each compartment by fluid being imbibed through the wall into each compartment at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall against the drug formulation in each compartment thereby producing in each compartment a solution containing drug, and by the expansion and swelling of the hydrogel, whereby drug formulation is dispensed through their orifices at a controlled and continuous rate over a prolonged period of time.

Description

SIMULTANEOUS DELIVERY OF TWO DRUGS
FROM UNIT DELIVERY DEVICE

FIELD OF THE INVENTION

This invention pertains to an osmotic system manufactured in the form of an osmotic device. More particularly, the invention relates ~o an osmotic device that simultaneously delivers two drugs that are separ-ately housed and separa~ely dispensed through separate orifices for (a) obtaining the ~herapeutic benefits of each drug, ~b) lessening the incidence of adverse 15effects due to the incompatibility of differeTIt drugs, or (c) delivering two drugs that are difficult to deliv~r from a dispensing device.

BACKGROUND OF THE INVENTION

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It is frequently desirable to prescribe pharma-ccutical dosage forms containing at least two differen~ drugs for cbtaining the pharmacological benefits of each drug. The coadministration of certain drugs is prescribed often in ~5 fixed ratios for several reasons. ~or example, for drugs that have the same therapeutic effect but act mechanistically different on the body, such combinations may have the added therapeutic effect of both agents but less side effects, or the drugs may act synergistically and create a larger than additive effect. Also, drug combinations are prescribed for treatments where each individual drug address different symptoms of a particular medical situation. Although, a large number of therapeutic combinations could be provided, oten they can not be compounded in the same dosage form because each drug needs to be administered on a different schedule. The different schedule is needed because each drug , 7S~

has a different biologlcal half life and therapeut:Lc index and therefore each drug should be administered in separate dosage forms on a prescribed schedule that is speci:Eic for each drug. Thus, a drug that needs to be administered four times a day, should not be combined with a drug that should be adminis-tered once a day. These drugs are kinetically incompatible in a pharma-ceutical dosage form. Another reason why certain drugs cannot be combined is they may be chemically incompatible or unstable in the presence of each other. This kinetic or chemical incompatibility can be eliminated by the novel dosage form provided by this invention. For example, by using the dosage form provided by this invention, a regimen consisting of four times a day adminis-tration of drug can be transformed into a once a day administration such that the drug previously administered four times daily can be combined with a drug administered once daily. In other words, both drugs can be coadministered to the body at delivery rates that are matched to achieve each of their separate therapeutic plasma concentratiolls. Thus, in the light of the above presenta-tion, it will be appreciated by those versed in the dispensing art, that if a delivery device is made availahle for housing two or more different drugs at controlled and continuous rates in therapeutically effective amounts for ob-taining the benefits oE each drug, such a delivery device would have a defin-ite use and be a valuable contribution to the dispensing art.
OB~ECTS O~ T~IE INVENTION
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Accordingly, this invention seeks to provide an osmotic device that contributes to the dispensing art by making available a device that can dispense at least two different drugs at controlled rates for obtaining the pharmàcological and physiological benefit of each drug, and which device thusly represents an improvement and an advancement in the delivery arts.

In ano-ther aspect, this invention seeks to provide an osmotic device :Eor separately housing and separately dispensing at least two drugs that can separately dispense at independently controlled rates and independently continuously deliver two or rnore drugs to biologica.l drug receptors over a prolonged period of time.
In still another aspect, the invention seeks to provide an osmotic device having two compartments each containing a drug that can be from insoluble to very soluble in an aqueous fluid, and an expandable par-tition between the compartment, which expandable partition operates to diminish the volume occupied by the drug in each compartment, thereby delivering each agent from the device at a controlled rate over time.
In a still further aspect the invention seeks to provide an os-motic device that can administer independently two different drugs from two compartments separated by a layer of an expandable driving member formed of a hydrogel, and which device provi.des a comp:lete pharma-ceutical regimen for the two drugs to a warm-blooded animal for a parti-cular time period, the use of which requires intervention only for initiation and possîbly termination of the regimen.
Thus, the invention seeks to provide an osmotic device for ~0 dispensing separately two different drugs in known amounts per unit time, and which device can continuously maintain substantially the major amount of the drugs present in the device as a saturated solution throughout their period of release from the device.

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Addi-tionally -the invention seeks to p:rovide an osmotic device that can deliver separately two different drugs by using an expandable driving member that continuously increases its volume while correspondingly decreasing -the volume occupied by each drug for main-taining excess drug in the device over an increased length of time.
Thus in a first embodiment this invention provides an osmotic therapeutic device for the controlled delivery of bene-ficial drugs to a biological environment, the device consisting 0 essentially of:
a) a wall formed of a semipermeable materi.al permeable to the passage of an external fluid present in the environment and substantially impermeable to the passage of drug, the semipermeable wall surrounding and forming;
b) a first compartment containing a drug formula-tion that exhibits an osmotic pressure gradient across the semipermeable wall against an external fluid;
c) a second compartmen-t containing a drug formulation that exhibits an osmotic pressure gradient across the semipermeable 0 wall against an external fluid;
d) a partition positioned between the first and second compartments, which partition is formed of a hydrogel that expands in the presence of fluid;
e) a first orifice in the wall communicating with the first compartment and the exterior of the device for delivering drug formulation from the first compartment to the environment over a prolonged period of time; and, 5~
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- ~a -f) a secon(i orifi.ce in the wall communica-ting with the second compar-tment and the exterior oE the devlce for del;vering drug formulation :Erom -the second compar-tment to the environmen-t over a prolonged period of time.
In a second embodiment -this invention provides an osmotic therapeutic device for the controlled delivery of bene-ficial drugs to a biological environment, the device consisting essentially of:
a) a laminated wall formed of a semipermeable lamina in laminar arrangement with a microporous lamina, the laminated wall surrounding and forming;
b) a first compar-tment containing a drug formulation -that exhibits an osmotic pressure gradient across the laminated wall against an external fluid;
c) a second compartment containing a drug formula-tion tha-t exhibits an osmotic pressure gradient across the laminated wall against an external fluid;
d) a partition positioned be-tween the first compartment and the second compartment, which parti.tion is formed of a hydrogel 0 -that expands in the presence of fluid;
e) a first orifice in the laminated wall communicating with the first compartment and the exterior of the device for delivering drug formulation from the first compartment to the environment over a prolonged period of time; and, f) a second orifice in the laminated wall communicating with the second compartment and the exterior of the device for delivering drug formulation from the second compartment to the environment over a prolonged period of time.

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- 4b -O-ther features and advan-tages of ~.he i.nven-tion will be more apparent -to those versed in the art from -the following specifiGation, taken in conjunction with -the drawings and -the accompanying claims.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings figures, which are not drawn to scale, but are set forth to illustrate various embodiments of the invention, the drawing figures are as follows:
Figure 1 is a view of an osmotic device designed and adapted for orally administering two beneficial drugs;
Figure 2 is an opened view of the osmotic device of Figure 1 illustrating the structure of the device comprising a semipermeable wall.;
Figure 3 is an opened view of the osmotic device of Figure 1 illustrating the device comprising a laminated wall;
Figure 4 is an opened view of the osmotic device of Figure 1 illustrating the structure and the operation of the device made with an added lamina;

~, l~B :~7~4 Figure 5 represents the cumulative weight gain, as a function of time, of a polymer disc enclosed in a semipermeable membrane when the disc is submersed in water;

Figure 6 is a graph depicting the percent weight uptake that polymers A, B, C, and D respectively exhibit in a sa~urated solution of sodium chloride in water as a function of their osmotic imbibation pressures;
Pigure 7 is a graph illustrating the cumulative amount of drug released from one compartment of a device;
and, lS Figure 8 is a graph illustrating ~he cumulative amount of drug released from the other compartment of the device.

In the drawings and specification, like parts in rela~ed figures are identified b~ like numbers. The terms appearing earlier in the specification and in the description of the drawings, as well as embodiments thereof, are further described elsewhere in the disclosure.
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-6- A~C 7S4 DETAIL~D DESCRIPTION OF THE DRAWINGS
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Turni~g now to the drawings in detail, which are an example of various osmotic delivery devices provided by the invention, and which example i5 not to be con-sidered as limiting, one example is the osmotic device illustrated in Figures 1 through 4 and designated by the numeral 10. In Figure 1, osmotic device 10 comprises a body 11 having a wall 12 with a first orifice 13 in wall 12 and a second orifice 14 in wall 12 for communi-cating the exterior of de~ice 10 with the internal lumen of device 10.-Wall 12 of osmotic device 10, as seen in opened section in ~igure 2, comprises a semipermeable material that is permeable to the passage of an external fluid and it is essentially impermeable to the passage of drug and osmagent. Wall 12 is substantially inert, it maintains its physical and chemical integrity during the dispensing of the beneficial drugs, and it is non-toxic to animals including humans. Wall 12 of osmotic device 10, as seen in an embodiment in opened-section in Figure 3, comprises a laminate formed of semipermeable lamina 12a in laminar arrangement wi~h a microporous lamina 12b. Mlcroporous lamina 12 b consists of micropores 12c that are preormed micropores, or the micropores are formed in the environment of use. Microporous lamina 12b is formed of materials that are inert and non-toxic. In Figure 3, device 10 is manu-factured in the embodiment illustrated with microporous lamina 12b facing the inside of device 10, and with the semipermeable lamina 12a facing the exterior of device 10.
In another embodiment, device 10 can be manufactured with microporous lamina 12b positioned outside facing the environ-ment of use and with semipermeable lamina 12a positioned

3; inside of device 10. Both the semipermeable lamina and the microporous lamina can contain additional wall forming agents such as flux enhancers, flux reducers, plasticizers~
and the like.

In Figure 3, device 10 is seen in opened-sec~ion for illustrating the structure of device 10.
While the internal structure of Figure 3 is described in detail, it is understood the detailed description can be applled to ~igure 2. In Figure 3, wall 12 surrounds and forms an internal lumen divided into a first compartment 15 and a second compartment 16.
Compartment 15 and compartment 16 are separated by a partition 17 formed of an expandable, swellable hydrogel material. Pirst orifice 13 communicates with first compartment 15 and second orifice 14 communicates with the second compartment 16. Compartment 15, in one embodi-ment, contains a beneficial drug 18, represented by dots, that is soluble to very soluble in an ex~ernal fluid and it exhibits an osmotic pressure gradient across wall 12 against the fluid 19, indicated by dashes, that is imbibed into first compartment 15. First compartment 15, in another embodiment contains drug 18 that has limited solubility or it is substantially insoluble in fluid 19 imbibed into cOmpartment 15, and it exhibits a limited, or it may not exhibit any osmotic pressure gradient across wall 12 against the exterior fluid. In this latter embodiment, drug 18 optionally is mixed with an osmagent 20, indicated by wavy lines, that is soluble in ~he external fluid and it exhibits an osmotic pressure gradient across wall 12 against the fluid. Second ccmpartment 16 contains a different drug 21 than the drug in the first compartment. Drug 21 is soluble to very soluble in the external fluid and it exhibits an osmotic pressure gradient across wall 12 against the fluid that is imbibed into second compartment 16. In another embodiment, drug 21 has limited solubility, or it is substantially insoluble in the fluid imbibed in compartment 16, and it exhibits a limi~ed, or it may not exhibit any osmotic pressure gradient across wall 12 against the exterior fluid. In this embodiment, drug 21 3 optionally is mixed with an osmagent 20 that is soluble in the external fluid and exhibits an osmotic pressure gradient across wall 12 for aiding in dispensing drug 21 from the device. The osmagent can be the same or different in the first compartment and the second compartment.

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Partition 17 in device lO is made of a hydrogel material. Hydrogel partition 17 possesses osmotic prop-erties. Partition hydrogel 17 absorbs fluid imbibed 5 into device' 10 and swells or expands to some equilibrium state. At equilibrium the osmotic pressure of the hydro-gel approximately equals the swelling pressure of the hydrogel, and the osmotic pressure of the hydrogel net-work is the driving force of the swelling, expanding partition 17 as it moves into compartment 15 and compart-ment 16 to urge drug formulation through orifice 13 and orifice 14 for delivering from device 10. That is, device 10 releases drugs through oriices 13 and 14 by fluid being imbibed into device 10 in a tendency towards osmotic equilibrium at a rate determined by the per-meability o wall 12 and the osmotic pressure gradient across wall 12. The imbibed fluid continuously forms a solution containing drug in each compartment, or a solution of osmagent containing drug in suspension in the compartments, which solution in either instance in both compartments is released by the combined operations of device 10. These operations include the solution being osmotically delivered through orifices 13 and 14 due to the continuous formation of solution in the compartments 7 and by the hydrogel swelling, increasing in volume, and applying pressure against the solutions "
in the compartments, thereby delivering the drugs to the exterior of device 10.

Partition hydrogel-17 operates to substantially insure that drug is delivered from each compartment at a constant rate over a prolonged period of time by two methods. First, the hydrogel operates to continuously concentra~e drug in each compartment by imbibing some fluid from each compartment to keep the concentration of the drugs from falling below saturation. Secondly, the hydrogel by imbibing external fluid across the wall -9- ARC 75~

continuously increases its volume, thereby exer~ing a force on drug 18 and drug 21 and diminish the volume of S compartments 15 and 16, thusly concentrating drug 18 and drug 21 in compartments 15 and 16. The swelling and expansion of the hydrogel, with its accompanying increase in volume, along with the simultaneous, corresponding reduction in volume of the compartments, assures the delivery of drug 18 and drug 21 at a controlled rate over time.
The osmotic delivery system as seen in Figures 1 through 3 can be made into many embodiments including the presently preferred embodiments for oral use, that is, for releasing locally or systemically acting therapeutic lS medicaments in the gastrointestinal tract over a prolonged period of time. The oral system can have various conventional shapes and sizes such as round with a diameter of 1/8 inch to 1/2 inch, or it can be shaped like a capsule having a range of si~es from triple zero to zero, and from 1 to 8.
2G In these manufactures system lO can be adapted for adminis-~ering drug to numerous animals, including warm blooded mammals, avians, reptiles and pisces.

While Figures 1 through 3 are illustrative of various delivery systems that can be made according to the invention, it is to be understood these systems are not to be considered as limiting, as the system can take a wide variety of shapes, sizes and designs adapted for delivering ~he drug to different biological environments of use. For example, the delivery system includes anal-rectal, artificial gland, blood system, buccal, cervical, dermal, ear, implant~
intrauterine, nasal, subcutaneous, vaginal, and the like.

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~ ARC 754 DETAILED DESCRIPTION OF THE INVE~TIO~

In accordance with the practice of this invention it has now been found an osmotic delivery system can be made for delivering at least two different drugs independently and simultaneously to a biological environment of use. ¦The delivery srstem comprises the two compartments as seen in Fi~ures 1 to 3 discussed above, with the drugs delivered independently from each compartment. The system described here is made with the same membrane composition and thickness on each compartment. The delivery equation for each osmotic compartment is giveTI by equation 1.
dm _ K A ~ ~ S~

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wherein K is the water permeability constant for the wall, A is the area of exposed surface o a compartment, ~ is the difference between the osmotic pressure in a compartment compared with the external osmotic pressure, SD is the solubility of the drug in fluid that enters the compartment, and h is the thickness of the wall of the device. The ratio of release rates from compartment 1, the first compartment, to compartment 2, the second compartment, is given by equation 2.

dm Kl Al ~1 SDl A ~ S
dm K2 A2 ~2 D A2 ~ ~ ~2) - - h wherein the K, A, ~, and SD are as defined, and the wall 3~ on compartment 1 and compartment Z are similar for homogenous walls, that is, ~he wall permeability Kl a K2, and the wall thickness hl = h2 , wherein hl is the wall thickness of 75 ~
~ ARC 754 compartment 1, and h2 is the wall thickness of compart-ment 2. Equation 2 reveals that the ratio of delivery S of one drug from one compartment to another drug from the other compartment is dependent only on the properties of the drugs, theim associated osmagents, and surface areas of the compartments. The rela~ive release rate from each compartment is modified or changed, by changing the composition in each compartment, and not the composition of the wall.
Alternatively, the two compartments can be manufactured to have separate wall compositions and/or thicknesses such ~hat the two rates can be engineered independently of eacn other using also the membrane properties. Such a structure can be achieved by coating the total system with the same membrane and subsequently layering a separate laminate with thickness h3 onto either compartment tl) or ~2), as illus~rated in Figure 4, wherein hl is the thickness of the wall surrounding the first compartment, h2 is the thickness of the wall at thec second compartment 9 and h3 is the thickness of the lamina added to the second compartment. Lamina h3 can be formed of a diferent semipermeable material, a material impermeable to fluid, a material that bioerodes over time, and the like.

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The materials forming the semipermeable wall of the delivery dévice are those that do not adversely affect the drug and the osmagent, an animal body, or other host, is permeable to an external fluid, such as water and biological fluid, while remaining essentially impermeable to drug, osmagents, and the like. The selectively permeable materials ~orming wall 12 are insoluble in body fluids, they are non-erodible, or thay can be made to bioerode after a predetermined period with bioerosion corresponding to the end o the drug release period. Typical ma~erials for forming wall 12 include semipermeable materials known to the art as osmosis and reverse osmosis polymers. The semipermeable polymers lS lnclude cellulose acylate, cellulose diacylate, cellulose tri-acylate, cellulose acetate, cellulose diacetate, cellulose tri-acetate, beta-glucan acetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamide, polyurethane 9 sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate, cellulose acetate valerate, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, selectively permeable polymers formed by the coprecipitation of a polycation and a polyanion as disclosed in U.S. Patent Numbers 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142. Generally, semipermeable materials useful for forming wall 12 will have a fluid permeability of 10-5 to 10 1 ~cc mil/cm2 hr atm) expressed per atmosphere of hydro-static or osmotic pressure across wall 12 at the temperature of use. Other suitable materials are known to the ar~ in U.S. Patent Numbers 3,845,770; 3,916,899; 4,036,228 and

4,1l1,202.

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The microporous matcrials comprising microporous lamina 12b maintains their physical and chemical integrity during the period of time drug is released from system 10.
The microporous materials comprising lamina 12b generally can be described as having a sponge-like appearance that provides a supporting structure for microscopic sized inter-connected pores or voids. The materials can be isotropic wherein the structure is homogenous throughout a cross-sectional area, the materials can be anisotropic wherein the structure is non-homogenous throughout a cross-sectional area, or the materials can have both cross-sectional areas.
The materials are opened-celled, as the micropores are continuous or connected~ with pores having an opening on both faces of the microporous lamina. The micropores are interconnected through tortuous paths of regular and irregular shapes including linear, curved, curved-linear, randomly oriented continuous pores, hindered connected pores, and other interconnected porous paths discernable by microporous e~amination.
Generally, the microporous lamina are character-ized as having a reduced bulk density as compared to the bulk density of the corresponding non-yorous microporous lamina.
The morphological structure of the total microporous wall have a greater proportion of total surface area than the non-porous wall. The microporous wall can be further characterized by the pores size, the number of pores, the tortuosity of the microporous paths, and the porosity which relates to the size and the number of pores. Generally, material possessing from 5% to 95% pores, and having a pore size of from 10 angstroms to 100 microns can be used for making the micropor~us lamina.

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Materia.ls useful for making the microporous lamina include polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups recur in the polymer chain, microporous materials prepared by the phosgenation of a dihydroxyl aromatic such as bisphenol, a microporous poly(vinylchloride), microporous polyamides such as polyhexamethylene adipamide, microporous modacrylic co-polymers including those formed from poly(vinylchloride) and acrylonitrite, microporous styrene-acrylic and its copolymers, porous polysulfones characterized by diphenylene sulfone in a linear cnain thereof, halogenated poly(vinyl-idene), polychloroethers, acetal polymers, polyesters prspared by esterification of a dicarboxylic acid or anhy-1 dride with an alkylene polyol, poly~alkylenesulfides), phenolics, polyesters, microporous polysaccharides having substituted anhydroglucose llnits exhibiting a decrease permeability to the passage of water and biological fluids, asymmetric porous polymers, cross-linked olefin polymers, hydrophobic or hydrophilic microporous homopolymers, co-polymers or interpolymers having a reduced bulk densi~y, . and materials described in U.S. Patent Numbers 3,595,752;
3,643,178; 3,654,066; 3,709,774; 3,718,532; 3,803,601;
3,852,224; 3,852,388; and 3,853,601; in British Patent No. 1,126,849; and in Chem. Abst. Vol. 71, 427F, 22573F, 25 1969.
Additional microporous materials for forming microporous lamina 12b include poly(urethane), cross-linked chain-ex~ended poly(urethane), poly(imides), poly(benz-imidazoles), collodion, regenerated proteins, semi-solid cross-linked poly(vinyl-pyrrolidone), microporous materials prepared by diffusion of multivalent cations into poly-electrolyte sols, microporous derivatives of poly(styrene) such as poly(sodium-styrene-sulfonate), poly(vinyl benzyl trimethyl-ammonium chloride), microporous cellulosic acylates and the like microporous polymers are known in U.S. Patent Numbers 3,524,753; 3,565,259; 3,276,589; 3,541,055; 3,541,006;
3,546,14Z; 3,615,024; 3,646,178; and 3,852,224.

The pore-formers useful for forming the micro-porous lamina in the environment of use include solids and pore-forming liquids. The term pore-former as used herein also embraces micropath formers, and removal o the pore and/or pore-former leads to both embodiments. In the expression pore-forming liquids, the term for this invention generically embraces semi-solids and viscous fluids. The pore-formers can be inorganic or organic and the lamina forming polymer usually contains from 5 to 70~ by weight of the pore-former, and more preferably about 20 to 50% by weight. The term pore-former for both solids and liquids include substances that can be dissolved, extracted or leached from the precursor microporous wall by fluid present in the environment of use to form operable, open-celled type microporous lamina. The pore-forming solids ha~e a size of about 0.1 to 200 microns and they include alkali metal salts such as lithium carbonate, sodium chloride, sodium bromide, potassium chloride? potassium sulfate 7 potassium phosphate, sodium acetate, sodium citrate, and the like. Organic compounds such as polysaccharides including the sugars sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol and the like. They can be polymers soluble in the environment of use such as Carbowaxes~, Carbopol~, and the like. The pore-formers embrace diols, polyols~ polyhydric alcohols, polyalkylene glycols, poly-glycols, poly~ )-a]kylenediols, and the like. The pore-formers are non-toxic and on their removal from lamina 12b, channels and pores are formed through the lamina that fill with fluid present in the environment of use.
The partition between the first and second compart-ment is formed of a hydrogel, that is, a swellable, hydro-philic polymer. The hydrogels exhibit the ability to swell in the presence of water and retain a significant fraction of water within its struc~ure. In one embodiment, the 3; hydrogel polymers are lightly cross-linked~ such cross-links D~

being formed by covalent or ionic bonds, which hydrogels interact with imbibed water and aqueous biological fluids and swell or expand to some equilibrium state. The hydro-s gels can be of plant or animal origin, hydrogels prepared by modifying naturally occurring structures, or synthetic polymeric hydrogels. The polymers swell or expand to a very high degree, usually exhibiting a 2 to 50 fold volume increase. Hydrophilic polymeric materials useful for the present purpose include poly~hydroxyalkyl methacrylate~, poly(N-vinyl-2-pyrrolidone), anionic and cationic hydrogels, hydrogel polyelectrolyte complexes, poly~vinyl alcohol) having a low acetate residual and lightly cross-linked with a member selected from the group consisting essentially of glyoxal, formaldehyde, and glutaraldehyde, a mixture of cross-linked agar and carboxymethyl cellulose, methyl cellu-lose cross-linked with a dialdehyde, a water insoluble, wa~er-swellable copolymer produced by forming a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene~ propylene, butylene or isobutylene cross-linked with from 0.001 to about 0.5 moles of a polyunsaturated cross-linking agent per mole of maleic anhydride in the copolymer, water-swellable polymers of N-vinyl ].actams, and the like. Generally, the partition will have a thickness of about 2 to 30 mils and will function to maintain the integri~y of the first and second compartments.
Addi~ional hydrogel-orming agents that can be used for making the expandable partition include polysacch-arides, polysaccharides with basic, carboxyl or other acid groups such as natural gum, seaweed extract, plant exudate, seed gum, plant extract, animal extract, or a biosynthetic gum. Typical gel-forming agents include agar, agarose r algin, sodium alginate, potassium alginate, carrageenan, kappa-carrageenan, lambda-carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, guar gum, locust bean gum, quince psyllium, flax seed, okra gum, arabinoglactin, pectin, xanthan, scleroglucan, dextran, amylose, amylopectin, dextrin, and the like.

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Other hydrogel polymers presently preferred for forming the partition include poly(ethylene oxide) having a molecular weight of 100,000 to 5,000,000 and commercially available as Polyox~ polymer, hydrophilic hydrogels com-prising a carboxypolymethylene, a carboxyvinyl polymer avail-able as Carbopol3 polymer, Cyanamer~ polyacrylamides, cross-linked water-swellable indene-maleic anhydride polymers, Good-rite~ polyacrylic acid, starch graft copolymers, Aqua-keeps acrylate polymer, diester cross-linked polyglucan, and the like. The hydrogels are known to the prior ar~ in U.S. Pat. Nos. 3,865,108; 4,002,173; 4,169,066; 4,207,893, 4,211,681; 4,271,143; and 4,277,366, ana in Handbook of Common Polymers, by Scott and Roff, published by the Chemical Rubber Company, Cleveland, Ohio.
lS The polymers used for forming lamina h3 additionally include polyethylene, polypropylene, polyacrylonitrile, reginated protein, erodible polyglycolic acid, polyorthoester, and the like.
The expression orifice as used herein comprises means and methods s~itable for releasing the drug from each compartment. The orifice will pass throùgh the semipermeable wall, or through the semipermeable-microporous laminated wall for communicating each compartment with ~he exterior of the device. The expression includes passageway, or bore through wall formed by mechanical procedures or by eroding an erodible element, such as a gelatin plug in the environ-ment of use. Generally, for the purpose of the invention the orifices will have a cross-sectional area of 2 to 15 mils. A detailed description of osmotic orifices and the maximum and minimum dimensions for an orifice are disclosed in the U.S. Patent No. 3,845,770 and 3,916,899.

The osmagents, or osmotically effective compounds that can be used in the first compartment or in the second compartmen~ include organic and inorganic compounds or solutes that exhibit an osmotic pressure gradient across 3; the semipermeable wall, or the laminated wall against an external fluid. Osmagents, or osmotically effective compounds include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium acid phosphate, mannitol, urea, sucrose, and the like. Osmagents are known to the art in U.S. Pat. Nos. 3,854,770; 4,077,407; and 4,235,236.

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-18- ARC 7$4 The ~erm drug as used in the specification and the accompanying claims includes physiologically or pharma-cologically active substances that produce a localized or S systemic effect or effects in animals~ avians, pices and reptiles. The active drug that can be delivered includes inorganic and organic compounds without limitation, those materials that act on the central nervous system such as hypnotics, sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agen~s, analgesics, anti-inflammatory, local anesthetics, muscle contractants, anti-microbials, anti-malarials, hormonal agents9 contraceptives, sympathomimetics, diuretics, anti-parasites, neoplastics, hypoglycemics, nutritional agents, ophthalmic, electrolytes, and the like. The drug housed and delivered from each compartment in a presently preferred embodimen~ embraces a different drug in the first compartment and in the second compartment respectfull~, as represented by the following: anti-in~lammatory and anti-pyretic, anti-inflammatory and analgesic, bronchodila~or and vasodila~or, beta-blocker and diuretic, beta-blocker and vasodilator, beta-agonist and muscle relaxant, beta-adrenergic agonist and histamine receptor antagonist, and decongestant, beta-adrenergic stimulator and muscle relaxant, anti-hypertensive and diuretic, analgesic and analgesic antispasmotic and anticholenergic, tranquilizer and anticholenergi.c, anticholenergic and histamine receptor antagonist, and the like. The phrase drug formulation indicates drug, or drug mixed with an osmagent present in, or released from the de~ice to the environment of use.
~ xemplary drugs tha are very soluble in water and can be delivered by the devices of this invention include prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, isoproternol sulfate9 methamphet~mine hydrochloride, phenmetrazine 3; hydrochloride9 bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, ~ethascopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, metoProlol tartrate, cimetidine hydrochloride, and the like.

~ ~b ^19- ARC 754 ~xemplary drugs that are poorly soluble in ~ater and that can be delivered by the devices of this invention include diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anisindone, diphenadione erythrityl tetranitrate, dizoxin, isofurophate, reserpine, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methoerexate, acetyl sulfisoxazole, erythromycin9 progestins, esterogenic progestational, corticosteriod~, hydrocortisone, hydrocorticosterone ace~ate, cortisone acetate, triamcinolone, methyltesterone, 17~-estradiol, ethinyl estradiol, ethiayl estradiol 3-metbyl ether, prednisolone, 17~ hydroxyprogesterone acetate, 19-nor~progesterone, norgestrel7 norethindone, norethiderone, progesterone, norgesterone, noreehynodrel, and the like. The amount of drug in each compar~men~ generally is from 0.05 ng to 800 mg, with individual compartments containing l mg. 5 mg, lO0 mg, 250 mg, 500 mg, and the like. The beneficial drugs are known to the art in Pharmaceutical Sciences, by Remington, 14th Ed., l9~0 published by Mack Publishing Co., Eas~on, PA; ln An~erlc~ , 1976, published by J.B. Lippincott Co., Philadelphia, PA, in The Drug, The_ urse, The Patient, Including Current Drug Handbook, 1974-1976, by Palconer et al. published by Saunder Company, Philadelphia PA; and in Medicinal Chemistry, 3rd Ed., Vol. l and 2, by Burger, published by Wiley-Interscience, New York.
3~
The drug can be in varîous forms, such as uncharged molecules9 molecular complexes, pharmacologically acceptable salts such as hydrochlorides, hydrobromides, sulfate, laurylate, palmitate, phosphate, nitrite~ borate, acetate, maleate, tartrate, oleate, and salicylate. For acid drugs, salts of -20- AnC 754 metals, amines or organic cations, for example quaternary ammonium can be used. Derivatives of drugs such as esters, ethers and a~ides can ~e used. Also, a drug that is water insoluble can be used in a form that is a water soluble deriva~ive thereof to serve as a solute, and on its release from the device, is converted by enzymes, hydrolyzed by body pH or other ~etabolic processes to the original biologically active form.
The drug can be present in the compartment with a binder, dispersant, wetting agent, suspending agent, lubricant and dye. Representative of these include suspending agents such as colloidal magnesium silicant, collidal silicon dioxide, and calcium silicate; binders like polyvinyl pyrrolidone, and magnesium stearate, wetting agents such as fatty amines, fat~y quaternary ammonium salts, and the like. The drug can also be present in the compartments mixed with a dye for aiding in identifying the drug in each compar~ment.
The solubility o~ -a drug in the fluid that enters the compartments can be determined by known techniques. One method consists of preparing a saturated solution co~prising the fluid plus the dr~g as ascertained by analyzing the amount of drug presene in a definite quantity of the fluid. A simple apparatus for this purpose consists of a test tube of medium size fastened upright in a water bath maintained at constant temperature and pressure, in which the fluid and the drug are placed and stirred by a rotating glass spiral. After a given period of stirring, a weight of the fluid is analyzed and the stirring continued an an additional period o~ time. If the analysis shows no increase of dissolved drug after successive periods of stirring, in the presence of excess solid drug in the fluid, the solution is saturated and the results are taken as the solubility of the drug in the fluid. If the drug is soluble, an added osmotic~lly effective compound optionally may not be needed, if the drug has limited solubility in the fluid, then an osmotically 3~

~ D~
-Zl- ARC 754 effect.ive compound can be incorporated into the device.
Numerous other ~e~hods are available for the deter~ination of the solubility of a drug in a fluid. Typical methods used for the measure~ent of solubility are chemical and electrical conductivity. Details of various methods for determining ~olubilities are described in United States Public Health Service Bulletin, No. 67 of the Hygenic Laboratory; Encyclopedia 9~ L~IL~I~eh~æL~s~ Vol- 1 2 7 pages 542 to 556, 1971, published by McGraw-Hill, Inc,; and Encyclopedia ~ictionary of Physics, Vol. 6, pages 547 to 557~ l~62, published in Pergamon Press, Inc~ For the purpose of the invention, the phrase drugs with degrees of solubility as used herein indicates~drugs that are insoluble to very soluble in aqueous and biological fluids. Further for this purpose, an.insoluble arug indicates a solubility of les~ than 25 mg of drug in a ml of fLuid9 a poorly soluble drug i8 one that dissolves in the range oE
about ~5 mg to 150 mg of drug per ml of fluid, a soluble drug dissolves about 150 mg to 600 mg of drug per ml of ~luid, and ~ very soluble drug dissolves in excess of 600 mg of drug per ml of fluid. While ~he presently preferred embodimen~s have been described with reference to poorly or ve~y soluble drugs It i8 to be understood the device can be used to deliver other drugs.

Polymeric hydrogel imbibition pressure deter-minations can be used for salecting a hydrogel useful for the present purpose. A determination can be made by using the following procedure. A l/2 inch round die, fitted with a l/2 ~ inch diameter stainless steel plugs, is charged with a known quantity of polymer with the plugs extending out either end. The plugs and the die were placed in a Carver press with plates between 200 and 300F. A pressure of lO,000 to 15,000PSI was applied to the plugs.

AEter 10 to 20 minutes of heat and pressure the eLectrical heatin~ to the plates were turned off, and tap water circulated

5 through the plates. The resul~ing 1/2 inch discs were placed in an air suspension coater charged with 1.8 kg saccharide cores and coated with cellulose acetate having an acetyl content of 39.8% dissolved in 94:6 w/w, CH2C12/CH3OH, to yield a 3% w/w solution. The coated systems were dried overnight at 50C. The coated discs were immersed in water at 37C and periodically removed for a gravimetric determination of water imbibed. The lnltial lmb~it~on ~.ressure was c~lculated ~y using ehe water transmi~sion constant for the cellulose acetate, after normalizing imbibition values for membrane surface area 15 and thickness. The polymer used in this determination was the sodium derivative of Carbopol-934~ polymer, prepared according to the procedure of B~Fo Goodrich Service Bulletin GC-36, "Carbopol~ Water-Soluble Resins9" page 5, published by 8.F~
Goodrich, Akron, Ohio.
The cumulative wei~h~ gain values, y, as a function of time, t, for the water soluble polymer disc eoated with the cellulose acetate were used to determine the equation of the line y-c ~ bt + at~ passing through those points by a least square fitting technique.
The weig~t gain for the Na Carbopol-934 is given by equation a9 follows: Weight Gain equals 0.359 + 0.665t -0.00106t2wherein t is elapsed ti~e in minutes. The rate of water imb~bition at any time will be equal to the slope o~ the line, that i5 given by tha following equations:

dy = ~ ) dt dt 3j ~ = 0.665 - 0.00212t dt To determine the initial rate ~ water absorption the derivative i~ evaluated at~t=0, that i5 dy/dt = 0.665 ~l/min, which is equal to the coefficient b. Normalizing the imbibition rate for membrane surface area 2.86 cm and thickness 0.008 cm, imbibition pressure ~ may be determined from the following equation K ~ - 0.665 ~l/min x (60 min) x t 1 ml ) (Q.008 c~
hr 1000 Y1 2.86 cm2 and the knowledge of the water permeability constant k of the cellulose acetate used in the experiment. The K value ~or cellulose acetate used in this experiment calculated from NaCl imbibition values i~ found to be 1.9 x 10 7 cm2/hr atm.

Substituting into the calculated K~ expression (1.~ x 10-7 cm2/hr.atm)( ~) = 1.13 x 10-4 cm2/hr, ~ = 600 atm at t - 0.
25 As a method for evaluating the ePficiency of a polymer with respect to duration of zero-order driving force, the ~/O of water uptake was se1ected before the water flux values decreased to 90~ of their initial values. The value of the initial slope for the equation oE a straight line emanating from the % weight 8ained axis will be equal to the initial value of dy/dt evaluated at tsO, with the y intercept c defining the linear swelling time, with (dy/dt)O = 0.665 and the y intercept = 0.359, which yields y 5 0.665t + Q.359. In order to determine when the value of the cumulative water uptake is 90% of the initial rate, 3;

-Z4~ ARC 75A

the follo~ing expression is solved for t, 0.9 y at = w ~9 -0 00106 t2 + 0.665 t ~ 0-359 ~ o.9, and 0.665t + 0.359 solving fo~ t, -0.~0106t2 ~ 0.0665~ ~ 0.0359 = 0 t -0.0665 ~ ~(0.0665)~ - 4(-0.00106)(0.035~)]
~(-0.0010~) t - 62 min and the weight gain is -0.00106(62)2 ~ (0.665)(62) 0.359 3 38 yl~ ~ith the initial sample weight = 100 mg, thus (Qw/w). 9 x 100 ~ 38%. An example of such imbibition resul~s are s~o~n in ~igu~ 5, - -~0 The selection of a hydrogel for forming a partitionfurther can be made by determining the interaction at the hydrogel-water drug interface~ This can be ascertained by placing 2 a film formed of a hydrogel in contact with an aqueous solution containing drug, and sometimes an osmagent, and observing the modification of the hydrogel at the hydrogel-aqueous drug environ-ment. Modiication of the surface of the polymeric hydrogel, during operation of the device, in situ, leads to an in situ formed precipitate in its outer surface of the hydrogel, thereby indicating the hydrogel and the solution containing drug are suitable for operating as a partition in the device. A repre-sentative procedure that can be used consists in measuring the percent weight gain for various polymers immersed in a saturated solution of a drug or an osmagent. The procedure broadly indicates interface absorption activity. That is, if there is little 3~

g~:~

-25- ARC' 754 absorption by the polymer, there is correspondingly a Little gain in w~ight and the polymer is suitable for use as a partition.
Similarly, if there is a large gain in weight, indicating a large volume absoxbed, the polymer is not prefe.rred as a partition for a highly water soluble drug. Figure 6 represents the percent weight gain for 4 polymers i~nersed in a saturated solution of NaCl as a fun~tion of the imbibition pressur~ of the polymer.
In Figure 6, the polymers are as follows: A is Klucel H~
polymer; s is Polyox COAG~ polymer; C is C~rbopol-934~ polymer;
and D is Na Carbopol-334~ polymer. The samples were period-ically removed from the solution, and the sNrface solution blotted and the polymer weighed. The equilibrium weight gain is defined as that point where no further increase in weight was measured over time. Other methods that can be used for studying the hydrogel solution interface include rheologic analysis, visco-metric analysis, ellipsometry, contact angl~ measurements,21ectrokinetic determinations, infrared spectroscopy, optical microscopy, interface morphology and microscopic examination o an operative device.

The osmotic device of the invention is manufac-tured by standard techniques. For example, in one manu-acture, a drug and optionally an osmagent and other ingre-dients that may be housed in one compartment are rnixed into a solid, semi-solid, moist9 or pressed state by conventional methods such as ballmilling, calendering, stirring or roll-milling, and then pressed into a preselected shape. A
partition is formed by molding, spraying or dipping one surface of the pressed shape into the partition forming material. The second compartment is formed by pressing a drug, or optionally a drug and an osmagent into a preselected shape that corresponds to the above formed shape, and then intimately attaching it to the partition, or a drug and an osmagent can be pressed directly onto the partition. ~inally, the two compartments are surrounded with a semipermeable wall, 3' or they are surrounded by a laminated wall. Optionally, system 10 can be manufactured by first fabricating one compartment by pressing in a standard table~ing machine -26- A~C 754 a drug to form a predetermined shaped compartment, and while the first shaped-pressed compartment is in the tablet pressing ma-chine, a layer of a partition forming hydrogel is added thereto, and then the other compartment is formed by press-ing drug to first compartment. Finally, the two adjacent compartments are surrounded with a wall formed of a semi-permeable material, and a passageway is drilled through the wall into each compartment to form system 10 with two distinct compartments and two distinct orifices for dispen-sing two drugs from system 10. The compartment also can be joined by other methods including heat sealing, pressing, consecutively casting the compartments in a dual cavity mold, overlaying, and the like.

The walls, lamina and partition forming the system can be joined by various techniques such as high frequency electronic sealing that provides clean edges and firmly formed walls, lamina and partitions. A presently preferred technique that can be used for forming the wall is the air suspension procedure. This procedure consists in suspending and tumbling ~he drug or osmagent dual compartment forming device in a current o air and a wall forming, or lamina forming, composition until the wall or lamina is applied to the drug.
The air suspension procedure is well-suited for independently forming the walls and lamlna. The air suspension procedure is described in U.S. Pat. No. 2,799,241; in J. Am. Pharm. Assoc., Vol. 48, pages 451 to 459, l9S9; and ibid., VolO 49, pages 82 to 84, 1960. Other wall and laminating techniques such as pan coating can be used in which the materials are deposited by successive spraying of the polymer solution on the drug accompanied by tumbling in a rotating pan. Other standard manufacturing procedures are described in Modern Plastics Encyclopedia, Vol. 64, pages 62 to 70, 1969; and in Pharma-ceutical Sciences, by Reming~on, 14th Ed., pages 1626 to 1678, 1970, published by Mack Publishing Co., Easton, Penna.

'75~

The microporous lamina, in optlonal manufacturing embodiments, can be manufactured with microporous wall forming polymers that are commercially available, or they can be made by art known methods. The microporous materials can be made and then manufactured into a device by etched nuclear track-ing, by cooling a solution of flowable polymer below its freezing poing whereby solvent evaporates from the solution in the form of crystals dispersed in the polymer, and then curing the polymer followed by removing the solvent crystals, by cold or hot stretching of a polymer at low or high tem-peratures until pores are formed, by leaching from a polymer lS soluble pore forming component by use of an appropriate solvent, and by dissolving or leaching a pore former from the wall of a device in operation in the environment of use.
Processes for preparing microporous materials are described in ~y~ Polymer Membranes, by R.E. Kesting, Chapters 4 and S, 1971 published by McGraw Hill, Inc; Chemical Reviews, ~ Ultrafiltrat~ Vol. 18, pages 373 to 455, 1934; Polymer Eng. and Sci., Vol. ll, No. 4, pages 284 to 288, 1971;
J~ Appl. Poly. Sci., Vol. 15, pages 811 to 829, 1971; and in U.S. Pat. Nos. 3,565,259; 3,615,024; 3,751,536; 3,801,692;
3,852,Z24; and 3,849,528.

Generally, the semipermeable wall will have a thickness of 2 to 20 mils, with a presently preferred thickness of 4 to 12 mils. The partition between the compartment generally will have a thickness of 1 mil to 7 mils, with a presently preferred thickness of 2 to 5 mils.
In laminated walls, the lamina will have a thickness of 2 to 10 mils with a presently preferred thickness of 2 to 5 mils. Of course, thinner and thicker walls, lamina and partitions for use with numerous drugs and osmagents are within the scope of the invention.

t~7 L ~

Exemplary solvents suitable for manufacturing ~he wall and the lamina include inert inorganic and organic solvents that do not adversely harm the wall and`lamina materials, and the final system. The solvents broadly include members selected rom the group consisting of aqueous solvents, alcohols; ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic aromatics, heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate 7 isopropyl alcohol~ butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone 9 methyl propyl ketone, n-hexane, n~heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclo-hexane, cyclo-octane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, and mixttlres thereof such as acetone and water, acetone and methanol, acetone and ethyl -alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol, and mixtures thereof.

~ESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way, as these examples and other equivalent~ thereof will become apparent to those versed in the art in the light of the present disclosure, the drawings and the accompanying claims.

As osmotic delivery device for the controlled and continuous delivery of the two beneficial drugs hydralazine hydrochloride and metoprolol fumarate to a biological environment of use is made as follows: first, a reservoir forming composition for housing in one compartment is com-pounded from 50 mg of hydralazine hydrochloride, 208.5 mg of mannitol, 8 mg of hydroxypropyl methylcellulose and 8 mg of stearic acid by mixing the hydralazine hydrochloride and the mannitol and then passing the mixture through a 40-mesh screen, next, the hydroxypropyl methylcellulose is dissolved in a 70/30 ~w/w~) ethanol-water solution and the hydralazine-mannitol mix~ure added to the wet hydroxypropyl methylcellulose lS and all the ingredients blended for 10 minutes. Next, the blend is passed through a 10-mesh screen and spread on a tray and dried in a forced air oven at 50C for 18-24 hours.
The dried blend is passed through a 20-rQesh screen, placed in a mixer, and the stearic added to the blend and the mixing continued for 10 minutes.
A second reservoir forming composition comprising l90 mg of metoprolol fumarate, 8.4 mg of sodium bicarbonate, 10.6 mg of polyvinyl pyrrolidone and 3.2 mg of magnesium stearate is made by first mixing the metoprolol fumarate with sodium bicarbonate and passing the mixture through a 40-mesh screen, then~ the polyvinyl pyrrolidone is mixed - with 15 ml of an ethanol and 5 ml of water solution, and the freshly prepared polyvinyl pyrrolidone solution is added slowly with mixing to the metoprolol fumarate- -sodium bicarbonate mixture. The ingredients are mixed for 20 minutes, passed through a 10-mesh screen and dried in a forced air oven for 24 hours. Next, the dried blend is passed through a 20-mesh screen, placed in a mixer, the rnagnesium stearate added and the ingredients again blended 3; to yeild the reservoir composition.

D'7~

Next, 275 mg of the hydralazine drug formula~ion reservoir, as described above, is placed into a 7/16 inch biconvex oval tablet die, and the turret of the tablet com-pression machine turned until the load reaches the compress-ion poin~ with the drug formulation compressed into the shape of the die. The turret is reversed back to the loading position and 100 mg of polyethylene oxide is spread over the compressed drug formulation to form a partition. Next, the turret is turned to the compression point to assist in forming the hydrogel partition. Then, the turret is returned to the loading position, and 200 mg of the meto-prolol fumarate drug formulation is added to the die in contact with the partition, and the -formulation pressed against the partition. The two united compartments then were coated in an air suspension machine with a wall of semipermeable cellulose acetate with a wall forming composition comprising 40% cellulose acetate having an acetyl content of 32%, 42~ cellulose acetate having an acetyl content of 39.8~ and 18~ hydroxypropyl methyl-cellulose, dissolved in an 80 to 20 parts by weight oE a methylene chloride-methanol solvent. The two compartments are coated with the cellulose acetate to form a semipermeable wall having a thlckness of 7 mils. The coated compar~men~s are dried-in a forced air oven at 50C for one week.
Then, an oriEice is laser drilled through the wall into one compartment, and then an orifice is laser drilled through the wall communicating with the other compartment. The orifices have a diameter of 9 mils for delivering each drug from the device. The osmotic systems had an average release rate of 2 mg/hr for hydralazine hydrochloride, and a re- ~
lease rate average of 13 mg/hr for metoprolol fumarate.
Accompanying Figure 7 depicts the cumulative amount re-leased over a delivery period oE 24 hours for hydralazine hydrochloride, and Figure 8 depicts the cumula~.ive amount of metoprolol fumarate released from the device over 2~
3; hours. The bars on the graphs indicate the minimum and maximum values, or ~he total range of experimental da~a.

3'~S ~

The procedure of Example 1 is repeated and ~ device S is provided housing in the first compartment a drug for-mulation comprising 50 mg of hydralazine hydrochloride, 208.5 mg of mannitol, 8.0 mg of hydroxypropyl methyl-cellulose and 8.2 mg of stearic acid, and ~he drug formu-lation in the second compartment comprises 190 mg of meto-prolol fumarate, 10.2 mg of polyvinyl pyrrolidone and 3.0 mg of magnesium stearate.

The procedure of Example 1 is followed in this example. The osmotic, oral device provided by this example contains in the first compartment a drug formulation comprising 50 mg of hydralazine hydrochloride, 208.5 mg of mannitol, 8.0 mg of hydroxypropyl methylcellulose and 8.2 mg of stearic acid, and in the second compartment a drug formulation consisting essentially of 290 mg of oxprenolol sebacinate, 96.1 mg of sodium bicarbonate, 16.3 mg of polyvinyl pyrrolidone and 4.0 mg of magnesium steara~e. The oxprenolol sebacinate drug reservoir formulation is prepared by first mixing the oxprenolol sebacinate and sodiùm bicarbonate and passing the mixture through a 20-mesh sieve, mixing the polyvinyl pyrrolidone with ethanol-water solution and then adding the wet poly-vinyl pyrrolidone to the oxprenolol sebacinate sodium bicarbonate blend. Then, the just prepared wet granulation is passed through a number 10-sieve, and dried overnigh~
in a forced air oven at 50C. Next, the dried granules are passed through a number 20-sieve and the magnesium stearate added thereto. The coating and tableting pro-cedures are as set forth in Example 1. The device released hydralazine hydrochloride at the rate of 3 mg/hr and oxprenolol sebacinate at the rate of 8 mg/hr.

~ /~

The procedure of Example 1 is followed in this example to produce an osmotic device comprising a first compartment containing a hydralazine hydrochloride drug formulation, a second compartment containing a metropolol fumarate drug formulation and a partition consisting essentially of polyacrylamide hydrogel, sold under the trademark Cyanamer~ A 370, a hydrogel polymer of approxi-mately 200,000 mol. wt.

EXAMPLE S

The procedures of Examples 1 and 2 are followed for producing delivery devices housing separately in the compart-ments salbutamol and theophylline, chlordiazepoxide hydro-chloride and clidinium bromide, acetaminophen and oxycodone, pindolol and thiazide, clme~idine and salbutamol, burimamide and pirenzepine, cimetidine and propantheline, cimetidine and isopropamide, and ~he like.

~5 The procedure of Example 1 is repeated in this example with all conditions as previously described with the drug in the first compartment a member selected from the group consisting of a hypnotic, sedative, psychic energizer, tranquilizer, anticonvulsant, muscle relaxant, 3~ antiparkinson drug, analgesicj anti-inflammatory, anesthetic, muscle contractant, anti-microbial, antimalarial, hormone, sympathomimetic and diuretic, and the drug in the second compartment is a different drug selected from the same group.

3;

t~

The procedure of Example 1 is repeated in this example with' all the conditions as described except tha~
the device is designed as an ocular osmotic insert and the ophthalmic drug in the first compartment is pilocarpine hydrochloride and the drug in the second compartment i5 epinephrine hydrochloride.

The novel osmotic systems of this invention use means for the obtainment of precise release rates in the environment of use while simultaneously maintaining the integrity and character of the system. While there has been described and pointed out features of the invention as applied to presen~ly preferred embodiments, those skilled in the art will appreciate that various modifications, changes, additions and omissions in the systems illustrated and described can be made without departing from the spirit of the invention.
2~

Claims (18)

THE CLAIMS:

1. An osmotic therapeutic device for the controlled delivery of beneficial drugs to a biological environment, the device consisting essentially of:
a) a wall formed of a semipermeable material permeable to the passage of an external fluid present in the environment and substantially impermeable to the passage of drug, the semipermeable wall surrounding and forming;
b) a first compartment containing a drug formulation that exhibits an osmotic pressure gradient across the semipermeable wall against an external fluid;
c) a second compartment containing a drug formulation that exhibits an osmotic pressure gradient across the semipermeable wall against an external fluid;
d) a partition positioned between the first and second compartments, which partition is formed of a hydrogel that expands in the presence of fluid;
e) a first orifice in the wall communicating with the first compartment and the exterior of the device for delivering drug formulation from the first compartment to the environment over a prolonged period of time; and, f) a second orifice in the wall communicating with the second compartment and the exterior of the device for delivering drug formulation from the second compartment to the environment over a prolonged period of time.

2. The osmotic therapeutic device for the controlled delivery of beneficial drugs according to claim 1, wherein when the device is in operation in the environment of use, fluid from the environment is imbibed through the wall into (1) the first compartment in a tendency towards osmotic equilibrium at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall, thereby forming a solution containing drug that is delivered through the first orifice from the device at a controlled rate over a prolonged period of time, and into (2) the second compartment in a tendency towards osmotic equilibrium at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall, thereby forming a solution containing drug that is delivered through the second orifice from the device at a controlled rate over a prolonged period of time.

3. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 1, wherein the drug formulation in the first compartment comprises a dosage unit amount of drug and an osmagent.

4. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 1, wherein the drug formulation in the second compartment comprises a dosage unit amount of drug and an osmagent.

5. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 1, wherein the first and second compartments contain different drugs.

6. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 1, wherein the device is adapted for oral administration for delivering drugs to the gastrointestional tract.

7. The osmotic device for the controlled delivery of the beneficial drug according to claim 1 wherein the wall is formed of a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate, ethylcellulose and cellulose acetate butyrate.

8. The osmotic device for the controlled delivery of a beneficial drug according to claim 1 wherein the hydro-gel is cross-linked.

9. The osmotic device for the controlled delivery of beneficial drug according to claim 1, wherein the hydro-gel can expand from a rested to an expanded state in the presence of exterior fluid imbibed into the osmotic device, whereby through the combined operations of the external fluid being imbibed through the wall into the first compartment and the second compartment, and the expanding hydrogel, solution containing drug is delivered through the first orifice and the second orifice from the first compartment and the second compartment to the exterior of the device over time.

10. An osmotic therapeutic device for the con-trolled delivery of beneficial drugs to a biological environ-ment, the device consisting essentially of:
a) a laminated wall formed of a semipermeable lamina in laminar arrangement with a microporous lamina, the laminated wall surrounding and forming;
b) a first compartment containing a drug formulation that exhibits an osmotic pressure gradient across the laminated wall against an external fluid;
c) a second compartment containing a drug formulation that exhibits an osmotic pressure gradient across the laminated wall against an external fluid;
d) a partition positioned between the first compartment and the second compartment, which partition is formed of a hydrogel that expands in the presence of fluid;
e) a first orifice in the laminated wall communicating with the first compartment and the exterior of the device for delivering drug formulation from the first com-partment to the environment over a prolonged period of time; and, f) a second orifice in the laminated wall communicating with the second compartment and the exterior of the device for delivering drug formulation from the second compartment to the environment over a prolonged period of time.

11. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 10 wherein when the device is in operation in the environment of use, fluid from the environment is imbibed through the laminated wall into (1) the first compartment in a tendency towards osmotic equilibrium at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall, thereby forming a solution containing drug that is delivered through the first orifice from the device at a controlled rate over a prolonged period of time, and into (2) the second compartment in a tendency towards osmotic equilibrium at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall, thereby forming a solution containing drug that is delivered through the second orifice from the device at a controlled rate over a prolonged period of time.

12. The osmotic device for the controlled delivery of the beneficial drug according to claim 10, wherein the hydrogel expands from a rested to an expanded state in the presence of exterior fluid imbibed into the device, whereby through the combined operations of the exterior fluid being imbibed through the wall into the first compart-ment to form a solution containing drug, and into the second compartment to form a solution containing drug, drug is delivered through the first orifice and through the second orifice from the first compartment and the second compart-ment to the exterior of the device over a prolonged period of time.

13. The osmotic therapeutic device for the con-trolled delivery, of beneficial drugs according to claim 10 wherein the drug formulation in the first compartment comprises a dosage unit amount of drug and an osmagent.

14. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 10 wherein the drug formulation in the second compartment comprises a dosage unit amount of drug and an osmagent.

15. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 10 wherein the first and second compartments contain different drugs.

16. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 10 wherein the device is adapted for oral administration for delivering drugs to the gastrointestional tract.

17. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 10 wherein the semipermeable lamina faces the compartments and the microporous lamina faces the environment.

18. The osmotic therapeutic device for the con-trolled delivery of beneficial drugs according to claim 10 wherein the microporous lamina faces the compartments and the semipermeable lamina faces the environment.