CA1318825C - Plurality of tiny pills in liquid dosage form - Google Patents

Abstract

ABSTRACT OF THE INVENTION
A delivery system is disclosed for delivering a beneficial agent to an environment of use. The delivery system comprises a plurality of tiny dosage forms comprising a beneficial agent. The delivery system also comprises means for maintaining (a) the physical and chemical integrity of the dosage forms and for (b) inhibiting delivery of the beneficial agent during non-performance of the delivery system.

Description

6 This invention pertains to a novel and useful drug delivery 7 system. More particularly the invention concerns a drug delivery 8 system comprising a plurality of tiny pills in a pharmaceutically 9 acceptable liquid carrier.

13 Tiny pills manufactured as small, round, solid dosage forms 14 comprising a medicinal agent surrounded by a film are known to the medical and t,o the pharmaceutical arts. The tiny pills known to the 16 prior art are delivered in a conventional manner tu a host dis~ersed 17 in a solid, dry carrier such as a compressed tablet comprising the 18 tiny pills, or a polymeric matrix comprising the tiny pills. In 19 another dosage fonm the prior art delivered the tiny pills housed in the dry lumen of a conventional capsule.

22 Tiny or small pills and dosage forms comprising tiny pills 23 in a dry tablet, matrix or dry capsule for dispensing a medicinal agent 24 are known in the following references: Lipowski, G. B. Pat. 523,594;
Laboratorie de Rechersches, G. B. PatO 1,098,006; Blythe, U. S. Pat.
26 No. 2,738,003; Svedres, U. S. Pat. No. 2,793,979; Wagner, U. S. Pat.
27 No. 2,897,121; Reese, U. S. Pat. No. 2,921,883; Swintosky, U. S.
2~ Pat. No. 2,951,792; Press, U. S. Pat. No. 2,g53,497; Barry, U. S.

~ 3~ 88~5 ARC 1511 1 Pat. No. 2,996,431; Sheppard, U. S. Pat. No. 3,080,294; Eng, U. S.
2 Pat. No. 3,081,233; Sheppard, ~. S. Pat. No. 3,109,775; Neville, 3 U. S. Pat. No. 3,139,383; Gaunt, U. S. Pat. No. 3,328,256; Speiser, U. S. Pat. No. 3,390,050; Chester, U. S. Pat. No. 3,492,397;
Raghunathan, U. S. Pat. No. 4,221,778; Urquhart and Theeuwes, U. S.
6 Pat. No. 4,434,153; Urquhart and Theeuwes, U. S. Pat. No, ~,578,075;
7 Urquhart and Theeuwes, U. S. Pat. No. 4,642,233; Urquhart and 8 Theeuwes9 U. S. Pat. No. 4,649,043 and Urquhart and Theeuwes, U. S.
g Pat. No. 4,659,558.
The dbove presentation teaches that delivery systems have 11 been provided to deliver tiny pills. While those delivery systems 12 provide for delivering the tiny pills, there are serious and inherent 13 short-comings associated with these delivery systems. For example, 14 tiny pills in a tablet may not be available for instant release to the lS environment of use. Tablets usually are made in a tabletting machine 16 under an applied pressure of a ton or more and this compressive force 17 absorbed by the tablet can seriously delay the release of the tiny 18 pills. Tiny pills dispersed in a polymeric matrix may not be available 19 because they are entrapped in the molecular structure of the polymer.
Additionally, well known serious shortcomings are associated with the 21 administration of dry capsules containing tiny pills. Dry capsules 22 are not a conducive means for administering a drug to a patient with a 23 dry or sore throat, they are bulky and hard to swallow, and they do 24 not lend thems~lves for administering a needed drug to children.
2S It will be appreciated by those versed in the dispensing art, in 26 view of the above presentation, that a critical need exists for a 27 delivery system for making tiny pills available instantly and con-2~ tinuously to an environment of use. The need exists for providing ` ~ 31 8825 67696-132 1 tiny pills for (a) achieving an early therapeutically effective plasma2 concentration of drug and for (b) achieving a continuous and therapeutic-3 ally effective plasma concentratlon of drug. A delivery system is 4 needed for housing and for providing tiny pills for (c) dispersing thedrug in a drug receiving environment for (d) increasing the bioavail-6 ability of the drug, (e) for concomitantly decreasing the llkelyhood 7 of local irritation of mucosal tissue, and ~f) for ma~king th~ unpleasant 8 taste of many drugs.
g SUMMARY OF THE INVENTION
_ 11 This invention seeks to provide both a nov~l and useful drug 12 delivery system that makes a substantial contribution to the art by providing a delivery system usefu1 for obtaining better therapy in the I4 management of health and disease.
~e present invention also seeks -bo provide a deliv~ry 16 system for both housing and delivering tiny pills, and which delivery 17 system overcomes the short-comings associated with the prior art.
18 ~he p~esent invention further seeks to provi~e a delivery 19 system for making available tiny pills throughout the environment of zo use for i~proving the availability and the absorption of a drug and 2I for minimizing local irritation of a biological drug receiving envi-22 ronment.
23 m e invention seeks to provide a delivery system 24 for administering tiny pills to the gastrointestinal tract with a del~ery system that is relatively economical in cost ~o manufacture, 26 provides the clinician in the hospital with a dependable delivery 27 system, and is well-adapted for practical and acceptable use in the 23 home, `-;,;.f'~

1 '[he present inv~ntion sccks to provid~ a d~ cry z system for administering d drug in the gastrointestinal tract by 3 making available a delivery system comprising a multiplicity of 4 miniature pills that spread and deliver drug over a large area of the gastrointestinal tract.
6 'l'hc present inv~ntion also sceks to provide a delivery 7 system comprising a multiplicity of orally administrable tiny pills 8 that are simple in construction and exhibit all the practical benefits 9 of controlled and continuous administration of drug in the stomach and in the intestine for executing a therapeutic program.
11 m e pr~sent invention seeks t3 provide a delivery 12 system comprising a plurality of tiny pills comprislng a drug, which 13 tiny pills are dispersed in a pharmaceutically acceptable liquid 14 carrier that exhibits means for substantially preventing a premature delivery of drug from the tiny pil1s while the tiny pills are in the 16 liquid carrier.
17 'l~e inven-tiQn also seeks to provide a FXEinmaceutically 18 acceptable carrier comprising a plurality of tiny pills wherein the 19 release of drug is delayed from the tiny pills by governing the pH of the carrier for preventing the loss of integr;ty of the walt of the 21 tiny pills.
22 The present invention seeks to proviae a delivery 23 system comprising d pharmaceutically acceptable liquid carrier housing 24 d mu1tiplicity of tiny p;lls wherein the liquid carrier suspends the tiny pi11s over time.
26 The presen-t invention seeks to provide a delivery 27 system comprising a plurality of tiny pills that can dispense at least 23 two different drugs at a controlled rate for obtaining the pharmaco-" ~i'' 1 3 1 8 8 2 5 67~9~-132 logical and physiological benefits of each drug, and which system thusly represents an improvement and an advancement in the delivery arts.
The present invention seeks to provide a delivery system housing tiny pills for dispensing two drugs essentially free of chemical interaction attribu~ed to chemical incompatibility, thereby overcoming the prohlems associated with the prior art.
The invention also ~eeks to provide a delivery system comprising tiny pills in a fluidic vehicle, and wherein the tiny pills exhibit prolonged storage and shelf life.
The invention provides a delivery system for ~he controlled delivery of a beneficial drug to an environment of use, the delivery system comprising:
A) a beneficial drug dispensing means comprising:
(1) a composition comprising a beneficial drug; and, (2) wall means for controlllny the release of the beneficial drug from the dispensing means, which wall means surrounds the composition;
B~ carrier means comprising a pharmaceutically acceptable liquid for housing a plurality of the beneficial drug dispensing means; and, (1) means in the carrier for delaying the release cf the beneficial drug ~rom the drug dispensing means.
The present invention further provides a delivery system for the controlled delivery of a beneficial drug to an animal, the delivery system comprisinrJ~
(a) a tiny pill comprising:

1 ;: 5 . ~

` 1 3 1 8 8 2 5 67696-132 (1) a composition comprising a beneficial drug, and (2) a wall comprising a composition for controlling the release of the beneficial drug from the tiny pill, which wall surrounds the composition comprising the beneficial drug;
(b) a carrier comprising a pharmaceutically acceptable liquid;
(3) a plurality of tiny pills in the carrier; and, (4) means in the carrier for delaying the release of the beneficial drug from the tiny pills.
Alternatively in the delivery system the tiny pill comprises a composition comprising a bene~icial drug and a wall for controlling the release of beneficial drug from the tiny pill, the wall surrounding the beneicial drug and comprising a semipermeable compositlon permeable to the passage of fluid.
In a further embodiment of the delivery system the wall for controlling the release of beneficial drug from the tiny pill and which surrounds the beneficial drug comprises an erodible composition that erodes in the environment of use. The liquid carrier also comprises means for slowing erosion of the erodible wall during storage of the tiny pill in the liquid carrier.
In another embodiment the wall that surrounds the beneficial drug comprises a release drug at a controlled rate by passage through the pores and the liquid carrier has means within for substantially decreasing the passage of drug through the pores.

5a ,~

~ 1 31 8825 676g~-l32 In another embodiment the wall comprises a composition that releases the drug by bursting a passageway ln the wall when the dellvery system is in operation in the animal tagether with means ln the liquid carrier for substantially preventing bursting of the passageway in the wall of the tiny pills during storage.
In another embodiment the wall comprlses a composition that releases the drug by metabolism of the wall when the pill is in operation in the animal. Neans are present in the liquid for substantially maintaining the physical and chemical integrity of the wall of the tiny pills during storage.
In preferred embodiments the liquid carrier comprises water, organic liquicl or a mixture thereof.
In the above embodiments when the wall comprises a drug release rate controlling composition there may be a pharmaceutically acceptable agent in the carrier which exhibi~s a concentration substantially equal to the concentration of drug in the tiny pills for delaying release of drug from the tiny pills.
~hen the wall comprises a composition permeable to the passage of fluid the carrier preferably exhibits an osmotic pressure substantially equal to the osmotic pressure exhibited by the drug in the tiny pills. The wall of the pill may comprise a composition permeable to the drug according to ~ick's Law of Diffusion.
In a further embodlment the tiny pill may comprise a composition including a pore former and the carrier may comprise means for substantially delaying removal of pore formed from the Sb ",~"

` 1 3 1 8 8 2 5 67696-132 wall during storage.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, whlch are not drawn to scale but are set forth to illustrate various embodiments of the lnvention, the drawing figures are as follows, Figure 1 depicts a container that can be used for contalning the delivery systems provided by the invention;
Figure 2 is an opened view of a container for depicking a dellvery system provided by the invention, which delivery system comprises tiny pills in a fluid medium;
Figure 3 is similar to Figure 2 wherein Figure 3 illustrates tiny pills that release a beneficial drug by an osmotic process;
Figure 4 is ~ view of a delivery system comprising tiny pills in a fluid which tiny pills release a drug by controlled disintegration;
Figure 5 is a view of a delivery system comprising tiny pills in 5c ,,; ' 1 31 ~825 ARC 1511 1 a fluidic means which tiny pills deliver a beneficial drug by the 2 process of diffusion;
3 Figure 6 is a view of a delivery system comF)rising tiny pills in 4 a fluid environment, which tiny pills release a beneficial drug through a microporous wall;
6 Figure 7 is a view of a delivery system comprising tiny pills in 7 a fluid environment, which tiny pills release a beneficial drug by a 8 process of erosion;
g Figure 8 illustrates a container with a pouring member useful for storing and then pouring the delivery system to a spoon, or the like, 11 for administering the delivery system to a patient;
12 Figure 9 is a graph depicting the osmotic bursting time for 13 delivery systems provided by the invention;
14 Figure 10 is a graph depicting the rate of delivery of drug from osmotic bursting delivery systems;
1~ Figure 11 depicts the rate of release from an osmotic bursting 17 aperture forming delivery system;
1~ Figure i2 depicts the effects of deformation on a wall of a 19 delivery system;
Figure 13 depicts the zero order rate of release from a delivery 21 system over time; and, 22 Figure 14 is an opened view for illustrating the structure of a 23 delivery system.
24 In the drawings and specifications, like parts in related drawing figures are identified by like numbers. The terms appearing earlier 26 in the specification and in the description of the drawings as well as 27 embodiments thereof are further described elsewhere in the disclosure.

t 31 8~25 ARC 1511 1DETAILED DESCRIPTION ~F THE DRAWINGS
2Turning now to the drawings in detail, which are an example of 3 the various delivery systems provided by the invention, and which 4 example is not to be construed as limiting, one example of a delivery system is seen in Figures 1 and 2. In Figure 1 a container 10 is 6 illustrated for housing the delivery system provicted by the invention.
7 The container can be any receptacle for holding a liquidJ and the 8 like, such as a bo~tle made of glass or plastic, a capsule, cup, beaker, and the like~
10In Figure 2 container 10 of Figure 1 is seen in opened-section at 11 11 for illustrating a lumen 12 that houses a delivery system provided 12 by the invention. The delivery system comprises a multiplicity of 13 tiny pills 13. Tiny pills 13 are a first dispensing means for the 14 control1ed delivery of a beneficial agent, such as a drug, both im-mediately and over a prolor,ged period of time. Tiny pills 13, an 16 agent dispensing means, comprise a core of beneficial agent 14, such 17 as d drug, surrounded by a wall 15 formed of a release rate controlling 18 material. Tiny pilis 13 can have a wall 15, in one embodiment, made 19 from a composition that releases beneficial agent 14 in the stomach, or tiny pills 13 can have a wall 15, in another embodiment, made from 21 an enteric composition which prevents release of beneficial agent 14 22 in the stomach, but will release beneficial agent 14 in the intestine.
23 Additionally, the composition comprising wall 15 can be selected, in 24 presently preferred embodiments, from wall-forming nontoxic composi-tions that release beneficial agent 14 by different physical-chemical 26 mechanisms. These mechanisms include osmosis, diffusion, erosion, 27 disintegration, metabolism, and like mechanisms. Wall 15 can have 23 various thicknesses as an additional aid for providing immediate timed 1 release and prolonged timed release of beneficia1 agent 14.
2 The de1ivery system provided by the invention comprises also 3 means 16. Means 16, a pharmaceutically acceptable carrier, comprises 4 a liquid and it is a second dispensing means for (a) containing tiny pills 13, (b) for delivering tiny pills 13 to an environment of use 6 such as a drug receptor, (c) for governing the release of beneficial 7 agent 14 from the tiny pills 13, and (d) for keeping the shelf life of 8 the tiny pills. Means 16 comprises a nontoxic, inert fluidic carrier g such as a member selected from the group consisting of an inorganic liquid, an organic liquid, aqueous media, emulsion, suspension, liquid 11 comprising semisolids, elixir, syrup, juice, osmotic solution, viscous 12 solution, hydrogel solution, gel suspension in a water media, pharma-13 cologically acceptable liquid, semisolid comprising a liquid and a 14 solid, and the like. Means 16, in a presently preferred embodiment, governs and substantially prevents a premature release of beneficial 16 agent 14 from tiny pills 13 into a liquid means 1~ in container 10.
17 Means 16 governs the release of beneficial agent 14 by exhibiting an 18 osmotic pressure or a concentration in a liquid means 16 that is 19 substantially equal to, or higher than the osmotic pressure or the concentration gradient exhibited by beneficial agent 14 across wall 15 21 of tiny pills 13 agairst liquid means 16. For example, for a benefi-22 cial agent 14 exhibiting an osmotic pressure of ~t~ or for a benefi-23 cial agent 14 blended with an osmotically effective solute exhibiting 24 an osmotic pressure of ~t~ the osmotic pressure exhibited by liquid means 16 is equal to ~L~ or greater than ~L~ such that ~L ~ ~t' where 26 ~t iS the osmotic pressure of the tiny pills. This inventive feature 27 provides also means for storing the delivery system essentially-free 2~ of drug release during storage.

1 31 8~25 ARC 1511 l The osmotic pressure or the concentration of liquid means 16 can 2 be regulated by adding a composition of matter to liquid means 16.
3 The composition of matter can be in any physical form such as powder, 4 particle, crystal, strip, film, granules, fiber, and the like. The composition of matter additionally can comprise a beneficial agent, an 6 osmagent or an osmopolymer. Osmagents are known also as osmotically 7 effective compounds and as osmotically effective solutes. The benefi~
8 cial agent can be a drug that is the same or different than a drug in g a tiny pill. Representative osmagents useful for blending with the liquid include carboxylic acids such as dicarboxylic, trtcarboxylic, 11 hydroxydicarboxylic, hydroxytricarboxylic and dihydroxycarboxylic 12 acids such as tartaric, citric, maleic, succinic, fumaric, mixtures 13 thereof, and the like; examples of osmotically active solutes include 14 solutes such as sodium chloride, magnesium sulfate, magnesium chloride, potassium chloride, sodium sulfate, lithium sulfate, potassium acid 16 phosphate and the like; carbohydrates such as raffinose, succrose, 17 glucose, lactose, galactose, altrose, monosaccharides, disaccharides, 18 polysaccharides, mixtures thereof, and the like; examples of alcohols 19 include alcohols such as sorbitol also known as hexanehexol, mannitol and the like; examples of gels include such as gum Arabic, agar, 21 acacia, tragacanth, and the like; Other ingredients that can be added 22 to the liquid include urea, inositol and like osmotic solutes.
23 The osmotic solute is present in any physical form that is com-24 patible with a host~ and with the tiny pills. The osmotic pressure of a solution of variously osmotically active compounds and a solution of 26 a beneficial agent such as a drug used for making tiny pills is Z7 measured in a commercially available osmometer that measures the vapor 23 pressure difference between pure water and the solution to be analyzed - ~ 31 8825 ARC lS

1 and, according to standard thermodynamic principles, the vapor pressure 2 ratio is converted into an osmotic pressure difference. An osmometer 3 that can be used for the present measurements is identified as Model 4 320B, Vapor Pressure Osmometer, manufactured by the Hewlett Packard Co., Avondale, PA. Procedures for measuring osmotic pressure using 6 thermodynamic principles are disclosed in U. S, Pat. Nos. 4,160,020 7 and 4,576,604.
8 Figure 3 is an opened section depicting a delivery system pro-g vided by the invention. Figure 3 illustrates a plurality of tiny pills 13 that release a drug by osmotic principtes. In Figure 3, tiny 11 pills 13 comprise a wall 15 that releases a beneficial agent 14 by the 12 process of osmotic bursting over time. In a presently preferred 13 embodimentl beneficial agent 14 is a drug. The drug, in one embodi-14 ment, is present in the form of an osmotic solute, such as a thera-peutically acceptable salt, that exhibits an osmotic pressure gradient 16 across wall 15 against distilled water, or the drug can be mixed with 17 an osmotical1y effective solute that exhibits an osmotic pressure 18 gradient across walt 15 against distilled water. In Figure 3, in the 19 embodiment illustrated, fluidlc means 16 comprises a concentration substantially equal to or larger than the concentration of drug 14 in 21 tiny pill 13 thereby providing an initial concentration gradient 22 substantially equal to zero. The wall forming composition used to 23 manufacture wall 15 comprises those materials permeable to the passage 24 of an external fluid present in an environment of use and substantially impermeable to the passage of drug and osmotic solute. Typical mate-26 rials include a member selected from the group consisting of cellulose 27 acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, 23 cellulose diacetate, cellulose triacetate, cellulose acetate having a 1 degree of substitution, D.S., up to 1 and an acetyl content of 21%;
2 cellulose diacetate having a D.S. of 1 to 2 and an acety1 content of 3 21% to 35%; cellulose trtacetate having a D.S. of 2 to 3 and an 4 acetyl content of 35% to 44.8%; cellulose acetate propionate, cellu-lose acetate butyrate, ethyl cellulose semipermeable polyurethane, and 6 the like. The osmotic wall can be coated around the drug in varying 7 thicknesses by pan coating, spray-co~ting, Wurster~ fluid air-suspension 8 coating, coacervation techniques, and the like. The wall is applied g using organic solvents such as methylene chloride-methanol, methylene chloride-acetone, methanol-acetone, ethylene dichloride-acetone, and 11 the like. Osmotic wall forming materials~ and procedures for forming 12 the wall, and osmotic bursting procedures are disclosed in U. S. Pat.13 Nos. 2,799,241; 3,952,741; 4,014,334 and 4,016,880.
14 Drug 14, neat, or a combination of drug 14 and osmotically effec-tive solute ir. pill 13, in one embodiment, will have a particle si7e 16 of 0.1 to 1000 micron, and a present1y preferred particle si~e of 17 about 0.5 to 300 microns, average. Procedures for measuring the 18 surface area average diameter of agent solutes are reported in J. Am.19 Chem. Soc., Vol. 6, p 309, (1938); The Surface ~hemistry of Solids, by Gregg, 2nd Ed., (1961), published by Remhold Corp., New York; in 21 Absorption, Surface Area and Porosity, by Gregg et al., (1967), 22 published by Academic Press, New York; in Physical Absorption of 23 ases, by Yound et al., (1962), published by Butterworth and Co., 24 Ltd., London; and in Fine Particle Measurements, by Valla, (1959), published by Macmillan Co., New York.
26 Procedures For ascertaining the impermeability or the permeability 27 of a polymer film used for providing wall 15 of osmotic bursting pill23 13 are known to tne art in ~ London, Series A, Vol 148 ~ . , 1 (1935); J. Pharm. Sci., Vol. 55, pp 1224-29, (1966); in 2 Diffusion in Solids, Liquids and Gases, by Jost, Chapter XI, pp 436-3 88, (1960), published by Academic Press, Inc., New York. Procedures 4 for measure osmotic bursting aper~ure ~ormation in a polymeric film by the hydrostatic pressure in the pill exceeding the cohesive integrity 6 of the polymeric film, with the polymer wall 15, can be determined by 7 measurements predicted on pressure-deflection and mechanical behavior 8 measurement techniques reported in Modern Plastics, Vol. 41, pp 143-9 44, 146 and 186, (1964); Handbook of Common Polymers, by Scott et a., pp 588-609, (1971), published by CRC Press, Cleveland, OH; in Machine 11 Design, pp lOi-ll, (1975); in J. Sci. Instruments, Vol. 42, pp 591-12 96, (1965); and by measuring mechanical stress-strain patterns of 13 polymers using the Instron~ Testing Machine, available from the 14 Instron Corporation of Canton, MA.
In Figure 4 another delivery system is seen provided by the 16 invention. In Figure 4 tiny pills 17 comprise drug 18 surrounded by 17 wall 19 of tiny pill 17 initially present in fluidic means 160 Wall 18 19 in the illustrated embodiment comprises a composition consisting 19 essentially of a ~atty ester mixed with a wax. Representative fatty esters include a member selected from the group consisting of tri-21 glyceryl ester, glyceryl distearate, glyceryl tristearate, glyceryl 22 monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl 23 monolaurate, glyceryl didocosanoate, glyceryl tridocosanoatel glyceryl 24 monodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryl 26 trimyristate, glyceryl monodeconate, glyceryl didecenoate, and 27 glyceryl tridecenoate.
23 The wax, in one representative embodiment, included in the wall 1 forming composition is a member selected from the group consisting 2 essentially of beeswax, cetyl palmitate, spermacetic wax, carnauba 3 wax, cetyl myristate, cetyl cerotate, stearyl palrnitate, stearyl 4 myristate, and lauryl laurate.
The tiny pills provided by the invention, in presently preferred 6 optional embodiments, can comprise an enteric coat. The enteric coat 7 can be in contact with the outer surface of the wall comprising the 8 tiny pill, or the wall can be made of an enter1c composition. The g entcric coat is made from an enteric ma~erials that do not dissolve or disintegrate in the stomach during the period of time the tiny pill ll passes through the stomach. The enteric materials suitable for 12 forming enteric coat or wall include: (a) entPric ma~erials that are 13 digestible by enzymes in the small intestine; (b) enteric materials 14 containing an ionizable polyacid; (c) enteric materials that are a long-chain polymer with an ionizable carboxyl group~ and the like.
16 Representative enteric materials include: (d~ a member selected 17 from the group of phthalates consisting essentially of cellulose 18 acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl 19 phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ester 21 phthalate, cellulose ether phthalate, hydroxypropyl cellulose 22 phthalate, alkali salts of cellulose acetate phthalate, alkaline earth 23 salts of cellulose acetate phthalate, calcium salt of cellulose 24 acetate phthalate, ammonium salt of hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxpropl methyl-26 cellulose hexahydrophthalate, polyvinyl acetate phthalate, and the 27 like; (e) a member selected from the group consisting of keratin, 23 keratin sandarac-tolu, salol, salol beta-napthyl benzoate and 1 acetotannin~ sa10l with balsam of Peru, salol with tolu, salol with 2 gum mastic, salol and stearic acid, and salol and shellac; (f) a 3 member selected from the group consisting of formalized protein, 4 formalized gelatin, and formalized cross-linked gelatin and exchange resins; (9) a member selected from the group consisting of myristic 6 acid-hydrogenated castor oil-cholesterol, stearic acid-mutton tallow, 7 stearic acid-balsam of tolu, and stearic acid-castor oil; (h~ a 8 member selected form the group consisting of shellac, ammoniated 9 shellac, ammoniated shellac-salol, shellac-wool fat, shellac-acetyl 1~ alcohol, shellac-stearic acid-balsam of tolu, and shellac-n-butyl 11 stearatel (i) a member selected from the group consisting of abietic 12 acid, methyl abietate, benzoin, balsam of tolu, sandarac, mastic with 13 tolu, and mastic with acetyl alcohol; ~j) a member selected form the 14 group consisting of cellulose acetate with shellac, starch acetate phthalate, polyvinyl acid phthalate, 2-ethoxy-5-(2-hydroxyethoxy-16 methyl)-cellulose phthalic acid, acid phthalates of carbohydrates, 17 zein, alkyl resin-unsaturated fatty acids-shellac, colophony, mixtures 18 of zein and carboxymethylcellulose, and the like. The enterlc 19 materials are discussed in Remington's Pharmaceutical Sciences, 13th Ed., pp 604-05, (1965), published by Mack Publishing Co., Easton, PA.
21 The composition comprising the ester and the wax can be coated 22 around the drug by using an organic solvent such as a member selected 23 from the group consisting of carbon tetrachloride, chloroform, tri-24 chloroethylene, ether, benzene, ethyl acetate, methyl ethyl ketone, 25 isopropyl alcohol, and the like. Tiny pills 17 are dispersed in a 26 carrier means 16 in which the tiny pills keep their integrity, such as 27 hypertonic emulsion. The fatty esters, waxes, solvent~s and procedllres 23 for making tiny pills that slowly disintegrate in d gastrointestinal t 3 1 8 8 2 5 ARC 1511 1 tract in a period of 8 to 12 hours are disclosed in U.S. Pat. No.
2 2,793,979, The tiny pills also can be stored in a liquid carrier 3 wherein the pH is adjusted to maintain the integrity of the tiny pills 4 during storage. For example, the tiny pills are stored in a low or high pH liquid means wherein the wall and the coat stay intact, and 6 when orally administered the wall or the coat contact the acid pH of 7 the stomach or the basic pH of the small intestine to release the 8 contents of the pills in the respectlve biological environment.
g Figure 5 depicts another delivery system provided by the inven-tion. In Figure 5 the delivery system comprises tiny pills 20, com-11 prising wall 22 that surrounds drug 21. Wall 22 is made of a drug 12 release rate controlling material. That is, drug 21 dissolves in wall13 22 and passes through wall 22 at a controlled rate over time. Tiny 14 pills 20 are stored in liquid means 16. The liquid means can comprisea pH or a media in which the drug is salted out of solution in the 16 wall at the liquid wall interface to delay diffusion of the drug 17 through the wall. On administration, the biological environment 18 allows the drug to diffuse through the wall for its intended 19 therapeutic effect.
Exemplary materials for forming drug release rate controlling 21 diffusional wall comprise ethylene vinyl acetate copolymer, polyethy-22 lene, cross-linked polyvinylpyrrolidone, vinylidene chloride-acryloni-23 trile copolymer, polypropylene, silicone, and the like. The wall can 24 be app1ied by the techniques described above and ma~erials suitable for forming wall 22 are described in U. S. Pat. Nos. 3,938,515;
26 3,948,262 and 4,014,335.
27 The rate of release of drug 21 through wall 22 can be determined23 easily by standard procedures. In this manner particularly materials 1 used as the wall as the drug release rate controlling barrier for 2 release of drug from the tiny pills can be selected. Various techni-3 ques, such as the transmission method, the sorption/desorption method, 4 and the like, can be used as measurers of permeability. One techniquethat has been found to be eminently well suited is to cast or hot 6 press a film of the material to a thickness in the rate of 1 to 60 7 mils. The film is used as a barrier between a rapidly stirred te. 9.,8 150 rpm) saturated solution of the drug and a rapidly stirred solventg bath, both maintained at constant temperature (typically 37C).
Samples are periodically withdrawn from the solvent bath and analyzed 11 for drug concentration. By plotting the agent's concentration in the 12 solvent bath, versus time, the permeability constant P of the material 13 is determined by the Fick's First Law of Diffusion.
14 P P (Q2 Q1)/(t2 ~ t1) ~ p AC/h, wherein Ql = cumulative amount of drug in receptor solvent at t1 16 Q2 = cumulative amount of drug in receptor solvent at t2 17 tl = elapsed time to first sample, i.e., Q1 18 t2 = elapsed time to second sample, i.e., Q2 19 A = area of membrane in cm2 C = initial concentration of drug 21 h = thickness of membrane in cm 22 By determining the scope of the plot, i.e., (Q2 ~ Ql)1(t2 - t1) 23 and solving the equation using the known or measured values of A, C, 24 ~ and h, the permeability P constant in cm2/time of the material for a given druy is readily determined.
26 The release rate through different drug release controlling 27 materidls can be easily ascertained by standard techniques known to 23 the art as recarded in J. ~harm._Sci., Vol. 52, pp 1,145 to 1,149; and 1 ibid., Vol. 53, pp 798-802, (1964); ibid., Vol. 54, pp I,459 to 2 1,464, (1965); ibid., Vol. 55, pp 840-43 and 1,224 to 1,239, (1966);
3 Encyl. Polyme_ Sci. TechnolO, Vols. 5 and 9~ pp 65-82 and 794-807, 4 (1968); the references cited therein, in U. S. Pat. Nos. 3,845,480;
3,845,761 and 3,896,819.
6 Figure 6 depicts another delivery system provided by the inven-7 tion. In Figure 6 the delivery system comprises tiny pills 23 com-8 prising wall 24 containing a pore forming agent 25, which wall sur-9 rounds a core of drug 26. Tiny pills 23 are dispersed in liquid means 1~. Wall 24 can be a wall forming material selected from the group 11 consisting of microporous olefin polymer, vinyl polymer, styrene poly-12 mer, acrylate polymer, acrylonitrile polymer, vinylidene polymer, 13 amide polymer, ester polymér, phenolic polymer, aldehyde polymer, 14 rubber polymer, organosilicon polymer, and the like. The polymer composition additionally contains a pore former that is leached from 16 wall 24 when the delivery system is in an environment of use. Rep-17 resentative pore formers comprise a member selected from the group 18 consisting of alkali metal salts, alkali earth metal salts, mono-19 saccharides, disaccharides, polysaccharides, polyalcohols and the like. In one presently preferred embodiment the pore formers comprise 21 the polyalcohols such as mannitol and sorbitol. In operation, in a 22 gastrointestinal tract, pore former 25 leaves wall 24 thereby provi-23 ding an exit port for drug 26 to be administered to the gastrointestinal 24 tract. The delayed release of drug 26 is effected by adding solubility modifiers to liquid 16, by buffering liquid 16 to delay the leaching 26 of a pore former 25, or by adjusting the pH of the liquid to a pH in 27 which a pore former is poorly or practically insoluble.
23 Figure 7 illustrates another embodiment provided by the inven-1 tion. In this embodiment tiny pills 27 comprise an erodible wall 28 2 that surrounds a core 29 of drug formulation. Wall 28 is made in a 3 preferred embodiment of a bioerodible polymeric composition that bio-4 erodes at a controlled and continuous rate in an environment o~ use.
Bioerodible materials useful for forming wall 28 include bioerodible 6 polyvalent acid or alkali mobile cross-linked polyelectrolyte, bio-7 erodible polycarboxylic acid, bioerodible polyester, bioerodible 8 polyamide, bioerodible polyimide, bioerodible polylactic acid, bioero-9 dible polyglycolic acid, bioerodible polyorthoes~er9 and bioerodible polycarbonates. The polymers used for manufacturing the wall are 11 selected in one embodiment based on the polymer's action in an acidic 12 or basic liquid member. For example, if hydrogen ions, or hydroxyl 13 ions start the erosion of the erodible polymer, the liquid is made 14 with an opposite ionic nature. A liquid member can be provided that corresponds to the liquid composition of the gastrointestinal tract 16 and, for example, if the polymer is acid labile the liquid member 17 comprises a neutral or a basic pH. The invention thus provides an 18 added embodiment for delaying the release of drug from a tiny pill by 19 governing the pH of means 16. The polymers and procedures for forming wall 28 are dlsclosed in U. S. Pat. Nos. 3,811,444; 3,867,519;
21 3,888,975; 3~971,367; 3,993,057 and 4,138,344. The erosion kinetics 22 of erodible polymers are known ln Controlled Release_of Bioactive 23 Materials, edited by 8aker, pp 1-17, published in 1980 by Academic 24 Press; CRC_Critical Reviews in Therapeutic Dru~ _arrier Systems, edited by Heller, Vol. 1, pp 39-90, (1984); Erodible Controlled 26 Release Systems, edited by Baker and Lonsdale, pp 235-242, published 27 by ACS, (1976); Controlled Release From Eridible Slabs, Cylinders and 23 Spheres, by Hopfenberg, pp 229-234, published by ACS, (1976); Blok.

1 J~ Int. Biodetn. Bull., 11 pp 78-84, (1975); and in Recent Advances 2 in Drug Delivery Systems, edited by Heller, pp 101-21, ~1984), pub-3 lished by Plenum Press, New York.
4 In the specification and in the accompanying claims the term, "beneficial agent" includes drugO The term, "druy" includes pharmaco-6 logically active substances that produce a loca7 or systemic effect in 7 animals, which term includes ~arm-blooded mammals such as humans. The 8 active drug that can be delivered includes drugs that act on the g central nervous system, depressants, hypnotics, sedatives, psychic energizers, tran~uilizers, anticonvulsants, muscle retaxants, anti-11 Parkinson agents, analgesics, anti-inflammatories, hormonal agents, 1Z anti-histamines, contraceptives, sympathomimetics, nasal decongest-13 ants, diuretics, anti-parasites, neoplastics, hypoglycemics, 14 opthalmics, electrolytes, cardiovascular drugs, and the like.
Exemplary drugs that are soluble in water and can be delivered by 16 the devices o~ this invention include prochlorperazine edisylate, 17 ferrous sulfate, aminocaproic acidt potassium chloride, mecamylamine 18 hydrochloride, procianamide hydrochloride, amphetamine sulfate, 19 benzhetamine hydrochloride, isoproternol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, 21 methacholine chloride, atropine sulfate, methascopolamine bromide, 22 isopropamide iodide, tridihexethyl chloride, oxprenolol hydrochloride, 23 methoprolol hydrochloride, cimetidine hydrochloride, dextromethorphan, 24 and the like.
Exemplary drugs that have limited solubility in water and can be 26 delivered by devices of this invention include meclizine hydrochloride, 27 phenoxybenzamine, thiethylperazine maleate, anisindone, erythrityl 2X titranitrate, dizoxin, reserpine, acetazolamide, methazolainide, _19_ 1 bendroflumethiazide, chlorpropamide, tolazamide, chlormadtnone acetate, 2 aluminum aspirin, methotrexate, acetyl sulfisoxazole, erytbhromycin, 3 progestins, estrogine, progestational, corticosteroids, and the like.4 Examples of other drugs that can be delivered by the devices include aspirin, indomethacin, naproxen, fenoprofent sulidac, diclo-6 Fenac, indoprofen, propanolol, metroprolol, oxprenotol, timolol, 7 clonidine, theophylline, ferrous lactate~ phenoxybenzamine, baclofen,8 furosemide~ and the like. The beneficial drugs are known in the art g in Pharmaceutical Sciences, by Remington, 14th Ed., 1979, published by Mack Publishing Co.; The Drug2 The Nurse, The Patient, Including 11 Current Drug Handbook, by Falconer et al., (1974-1976), pub1ished by 12 Saunder Company; and Medicinal Chemistry, 3rd Ed., Vols. 1 and 2, by 13 Burger, published by Wiley-Interscience Co.
14 The drug can be present in the tiny pill in various forms, such as unchanged molecules, molecular complexes, therapeutically acceptable 16 salts such as hydrochlorides, hydrobromides, sulfates, oleates, and 17 the like. For acid drugs, salts of metals~ amines, or organic cations, 18 quaternary ammonium salts can be used. Derivatives of drugs such as 19 esters, ethers and amides can be used. Also, a drug that is water insoluble can be used in a form that is the water soluble derivative 21 thereof to serve as a solute and, on its release from the device, is 22 converted by enzymes, hydrolyzed by body pH or other metabolic process 23 to the original biologically active form.
24 The amount of drug present ;n a tiny timed pill generally is from about 10 ng to 50 mg. The number of tiny pills in a given amount of 26 liquid means is from 10 to 1000 in, for example, a ml of liquid, or 27 more. The tiny pills comprising an exterior wall and an inner core of23 drug generally have a diameter of about 50 microns to a diameter of 1 4000 microns and in a presently preferred embodiment a diameter of at 2 least 200 microns. The wall thickness can vary as an aid in controlling 3 `the release of drug, with wall thickness exemplified as from 0.01 mm 4 to 3.00 mm and the like.
The fol1Owing examples are merely illustrative of the present 6 invention, and they should not be considered as limiting the scope of 7 the invention in any way, as these examples and equivalents thereof 8 will become apparent to those versed in the delivery art in light of g the present disclosure and the accompanying claims.

11 An orally administrable dosage form comprising tiny pills of a 12 cough suppressant housed in a liquid member is prepared as follows:
13 first, dextromethorphan hydrobromide and succinic acid in a ratio of 1~ 0-5 to 1 are b1ended and blended with hydroxypropylmethylcellulose in bead form, and then divided in three equal fractions of three different 16 sizes of 0.1, 0.2 and 0.3 mm radius. The spherical beads are coated 17 next with a wall forming composition. The composition comprises a 18 b1end of cellulose acetate having an acetyl content of 39~8~ and 19 cellulose acetate butyrate comprising an acetyl content of 29% and a butyryl content of 17%. The cellulose acetate and the cellulose 21 acetate butyrate are present in a 50:50 blend, the cellulose acetate 22 butyrate has a permeability k equal to 2 X 10 5 cm.mil/hr, and the 23 cellulose acetate has a permeability k of lO 4 cm.mil/hr. The wall 24 forming composition is applied from an organic solution containing methylene chloride and to the wall applied in a ratio of 1 to l.
26 Next, the solvent is stripped from the pills and the tiny pills per-27 mitted to dry at room temperature. Then the tiny pills are added to a 23 liquid means comprising 5 ml of lemon tincture, 5 ml of orange -2~-1 tincture, 0.5 gm sodium saccharide, 65 ml propylene glycol, 15 ml 2 glycerin and sorbitol solution to 100 ml. The dosage form optionally 3 can be stored in Container 30, as seen in Figure 8. Container 30 is 4 equipped with a pouring member 31 for delivering tiny pills 13 in liquid means 16 to a spoon, or the like, for administering to a 6 patient.

8 Another dosage form is prepared by following the procedure of 9 Example 1, except that in this example dextromethorphan and mannitol are blended as dry particles in a ratio of 10 to 1. The particles are 11 coated in a fluid air suspension machine with a composition of ethyl 12 cellulose in ethanol to surround the drug core with a wall of the 13 cellulose to yield tiny pills thereof. After the solvent is vacuum 14 stripped from the tiny pills, the pills are blended with a solution comprising sorbitol, propylene glycol, alcohol, water and orange oil.

17 Another dosage form is provided by coating a drug core composi-18 tion comprising phenylpropanolamine hydrochloride, lactose and magnesium l9 stearate in a fluid air suspension machine with a composition compri-sing ethyl cellulose in ethanol to surround the drug core with a wall 21 of ethyl cellulose to yield tiny pills thereof. After the solvent is 22 vacuum stripped from the tiny pills, the pills are blended with a 23 solution comprising sorbitol, propylene glycol, alcohol, water and 24 orange oilO

-26 The above manufacture can be repeated by replacing the ethyl 27 cellulose and ethanol with cellulose acetate having an acetyl content 2~ of 39% in methylene chloride-methanol wall-forming solvent; or by 1 applying a bioerodible wall of poly(2,2-dioxo-trans-1,4-cyclohexane 2 dimethylene tetrahydrofuran) around the drug core The latter bio-3 erodible polymer is applied by heating the polymer to 80-90C and 4 then coating the drug cores. The tiny pills in both manufacture are added to a hypertonic liquid means.

7 A dosage Form is manufactured by first preparing sustained 8 release tiny pills by blending 40 y of polyvinyl pyrrolidone with 9 375 g of theophylline, the blend kneaded and passed through an ex-trusion granulation machine to produce drug cores with an avera3e 11 radius of 0.1 ~n. After drying at 115-1209 the drug cores are 12 coated with a wall of ethyl cellulose in an air suspension machine to 13 yield tiny pills. The tiny pills are added to a liquid means compri-14 sing 0.8 g of powdered gelatin type A, 50 ml of edible oil and suffi-cient water to 100 ml. The liquid means is prepared by following the 16 procedure in Pharmaceut~cal Sciences, by Remington, 14th Ed., (1970), 17 p 1492, published by Mack Publishing Co., Easton, PA. The dosage form 18 can be used for orally administering the bronchodilator for the manage-19 ment of status asthmaticus and as a pulmonary vasodilator and smooth muscle relaxant. Other forms of theophylline can be used in the 21 subject dosage form such as theophylline sodium acetate, theophylline 22 sodium glycinate, ~7-(2,3-dihydroxypropyl)] theophylline, theophylline 23 meglumine, and theophylline monoethanolamine.

In another manufacture, the dosage form is made by first prepa-26 ring sustained release tiny pills by blending 400 ml of ethyl cellulose-27 water, 70:30 solution, 7.5~ w:v, with 375 9 of theophylline, 150 y of 23 mannitol and 475 9 of magnesium stearate and the blend kneaded and 2 passed through an extrusion granulation machine. After drying at 115-120 F, the core are passed through a 20 mesh screen and coated 3 with a wall of ethyl cellulose in an air suspension machine to yield 4 tiny pills. The tiny pills are added to a liquid means comprising 0.8 g of powdered gelatin type A, 0.8 9 of tartaric acid, 0.1 g of citric 6 acid, 0.1 9 of ascorbic acid, 6 ml of alcohol, 50 ml of edible oil 7 and sufficient water to 100 ml. The liquid means is prepared by 3 fo1lowing the procedure in Pharmaceutical Sciences, by Remington, 14th Ed., (1970), p 1492, published by Mack Publishing Co., Easton, PA. The dosage form can be used for orally administering the bronchodilator 11 for the management of status asthrnaticus and as a pulmonary vasodilator 12 and smooth muscle relaxant. Other forms of theophylline can be used 13 in the subject dosage form such as theophylline sodium acetate, 14 theophylline sodium glycinate, [7-(2,3-dihydroxypropyl)] theophylline, theophylline meglumine9 and theophylline monoethanolamine.

17 Other delivery systems comprising tiny pills are made by spraying 18 non~pareil cores with an edible adhesive and then dusting the adhesive coated core with a drug. The drug coated core then is coated with an appropriate edible enteric coat to provide enteric coated tiny pills.
21 In a preferred manufacture at least one enteric coat is applied in 22 this embodiment of the invention, but more than one coat, usually 1 to 23 20 separate coats, can be used for the present purpose. Manufacturing 24 procedures for tiny pills are taught in U. S. Pat No. 3,365,365.

26 In another embodiment the tiny pills can be made from a core of 27 carbohydrate, such as sucrose, dusted with a mixture of talc, starch 28 and galactose, moistened with distilled or deionized water, and -the 2~-1 31 ~382S ARC 1511 1 desired medicinal such as the antibiotic erythromycin. The pills are 2 dried and then coated with an outer layer of a nontoxic, enteric wall 3former selected from the group consisting of keratin, calcium alginate, 4 shellac, partially hydrolyzed styrene-maleic acid copolymer, poly-S vinylacetate phthalate, polyvinyl hydrogenphthalate, and the like.
6 Finally, the tiny pills are dispersed and/or suspended in an acidic 7 liquid means adapted for oral admittance into the gastrointestinal 8 tract. Procedures for manufacturing the tiny pills are described in 9U. S. PatO No. 3,081,233.

11A drug with an osmotic pressure of 100 atmospheres, atm, as 12 ascertained by using an osmometer, is granulated into particles of 13 various size radius from 0.1 to 0.5 mm. A wall forming polymer is 14 coated in a ratio of 1:1 onto thc drug. The elongation defined as the ratio of the increase in radius at bursting to the original radius of 16 the particle is 0.5. The polymer selected for the coating process can 17 have a variety of water sorption characteristics resulting in a water 18 content of up to 30 percent, or X = 0.3. The bursting time by osmosis 19 for each tiny pill is given in accompanying Figure 9. In Figure 9, Tb(Hr) is the bursting time in hours for a tiny pitl, Ro is the radius 21 in mm of the uncoated particle, and X is the fraction of water in the 22 wall. From Figure 9, it is clear that a total mass of formulation can 23 be prepared with various mass fractions of particle sizes which are 24 coated with various polymers of different elongation and water sorption.

26A drug delivery system is prepared comprising tiny pills in a 27 liquid means. The tiny pills deliver the drug by osmotic bursting of 2~ the wall to form in the gastrointestlnal environment d drug release 1 orifice in the wall of the tiny pill. The tiny pills were prepared 2 from osmotic particles of drug exhibiting an osmotic pressure of 40 3 atm, and the drug was shaped into spheres of 0.1, 0.2 and 0.3 mm. The 4 liquid means has an equivalent or higher osmotic pressure. The polymer comprising the wall had an elongation of 0.5 mm and a water 6 permeability of 25 X 10 8 cm2/hr. The drug has a density of 1.2 g/ml.
7 One gram of the drug exhibited a bursting time and a delivery rate 8 dependent of the radius of the particle as shown in accompanying 9 Figure 10. In Figure 10, RO(mm) is the radius of the particles in mm, and Rate ~gr/hr) is the rate of drug delivery in grams per hourO The 11 study indicates, from the accompanying Figure 1O, that a mixture of 12 particles can be provided to give a release rate given by Equation (a) 13 wherein fl~ f2~ f3 are in Equation (a~ the fraction of particles 14 present of rate R19 R2 and R33 respectively, 16 R = f1 R1 + f2 R2 + f3 R3 (a) 17 The drug dextromethorphan hydrobromide exhibits an osmotic pressure of 18 40 atm. The osmotic solute sucrose in aqueous solution is formulated 19 to an osmotic pressure exceeding 40 atm.

21 The delivery of a drug from a tiny pill that releases the drug by 22 osmotic bursting of the wall to provide a drug releasing orifice is 23 seen from the following presentation and the accompanying equations.
24 The tiny osmotic bursting pills in an aqueous media that is hypotonic compared to the compositon inside the tiny pills imbibes water into 26 the tiny pills. In the absence of a preformed orifice in the wall of 27 the tiny pill, the imbibed aqueous fluid causes the tiny pill to swell 23 and a volume increase occurs during which time period (~ t1) the t 3 1 8825 ARC 1511 1 delivery rate from the system is low. When the internal hydrostatic 2 pressure exceeds the pressure necessary to rupture the wall, ihe 3 release rate increases to a maximum during the period ~t2, after 4 which the rate a~ain decreases when all the solid excess drug from the S core is delivered. A typical curve depicted in Figure 11.
6 The release rate from the osmotic bursting tiny pills is des-7 cribed by Equation (1) with tdV/dt)t given by Equation (2).

dm = (dV) C + (dm) (l?

11 (dt)t h Lp ( ~ ~Q P) - (dV) (2) 12 wherein in Equation (1) and Equation (2), C is the concentration of 13 the drug sotution hydrodynamically pumped, (dm/dt)D is the amount 14 of drug delivered by diffusion through the wall, (dV/dt)t is the total IS volume of solution hydrodynamically pumped from the tiny pill which is 16 equal to the volume of water imbibed by the tiny pill as set forth in 17 Equation (3), minus the volume increase of the tiny pill per unit time 18 (dV/dt)V-dY _ A L (oQ~ -~ P) (3) (dt)j h P

22 Further, wherein A is the wall area, h is the wall thickness, a the 23 reflection coefficient of the wall, Q~ and Q P are the osmotic and 24 hydrostatic pressure difference between the inside and outside of the wall. From the time, t=0, a small amount of drug is usually delivered 26 in the absence of an orifice by diffusion through the wall as des-27 cribed by (dm/dt)D. During this time period, Qt1~ the volume 2;3 increase is equal to the volume imbibed, as set forth in Equation (3a) 2 dt j (dt)V and therefore (dV) = 0 ~3a) 3 The effect of the volume stretching during the period Q t1 is 4 twofold: 1. delay in delivery and 2. the system potential zero order S delivery profile is substantially shortened since the amount of drug 6 that is delivered at a non-zer~ order rate is seen in Equation ~4):

8 MNZ0 = S . V

9 wherein V is the volume at the time of bursting, which is larger than the undeformed volume. S is drug solubility. According to Equation (5) 11 the mass not delivered at zero order is:
12 ~NZ S [V0 + (aF)j ~tl~ (5) 14 since the volume deformation associated with Figure 11 is largely plastic or permanent deformation. Thus, by selecting the mechanical 16 properties of the wall and thereby controlling the function (dV/dt)V, 17 as a function of pressure or elongation, several release rate profiles 18 can be programmed for the tiny pi1ls as described by the basic spike 19 type curve obtained by plastic deformation of the wall as seen in Figure 11, and by selecting an élastic wall a curve can be obtained as 21 seen in Figure 12. In Figure 12, Qt is the elastic deformation, ~t2 2Z is the elastic recovery and Qt3 is the osmotic pump kinetics. Thus, 23 by selecting a brittle wall wherein early aperture formation occurs 24 without deformation, a zero order rate profile can be obtained for the tiny pills, as seen in Figure 13, wherein a is the brittle fracture 26 and b is the release rate for a conventional zero order curve.
27 Accompanying Figure 14 illustrates in opened section a tiny pill 28 designed -For releasing a drug by an osmotic bursting mechanism. In 1 3 t 8825 ARC 1511 1Figure 14, a pill 10 is seen comprising an osmotically active drug 2 core 32 surrounded by a semipermeable wall 33. In operation, when 3 pill 10 is in a water envirorment, it imbibes water by osmosis and the 4 internal volume increase per unit time is describecl by Equation (6):
5dV - k . A (~ P) (6) 7 wherein A is the area of the semipermeable wall, h is the thickness of 8 the wall, k is the permeation constant, a~ is the osmotic pressure 9 difference between the solution inside and outside the tiny pill9 and aP is the hydrostatic pressure differences between the inside and the 11 outside of the pill.
12The internal volume expands from YO~ the volume at time zero, to 13 Vb, the volume at bursting time, tb~ The bursting time is obtained 14 from Equation (6) and given by Equation (7):

16 ~ h.dV
17b VO k.A (~ - ap) 18The quantities h, k, A,~ , and P are all functions of volume;
19 and during the initial stages of swelling when the solution inside the system is saturated, Equation (8) holds:

~ o (8) 23 and when the osmotic pressure of the outside solution is negllgible, ~
24is the osmotic pressure inside the system up to a volume V, as expressed by Equation (9):

27 V = 5P
2~

13188~5 ARC 1511 1 wherein Mp is the mass of the drug particle and S is the solubility 2 of the drug. Thus, for most applica-tions, the volume at bursting Vb 3 is smaller than V as given by Equation (8) and Equation (9), The 4 quantities A, h, and V can conveniently be expressed as a function of S the system radius r as seen in Equation (10) and Equation (11):

A = 4 ~ r (10) V ~ ~r (11) Assuming that the drug wall deforms at constant volume results in 11 Equation (12):
12 r 2 13 h ( ) h - (12) 15 ~ For a thin wall~d system, the mass of the wall is given by 16 Equation (13):

18 Mc = 4 ~ rO ho-Pc (13) 19 wherein Pc is the density of the wall. The mass of the drug is given by Equation (14):

22 Mp = 4 . ~rO3 . Pp (14) 24 wherein pp is the density of the drug. The ratio of drug to the wall weight from Equation ~13) and Equation (14) is combined in Equation (15):

27 ~ rO . ~ (15) 2~ Mc 3 ho Pc l accompanied by the assumption Pp ~PC~ then Equatian (16) follows:

(16) MC 3 ho ~ Thus, for a soft walled system wherein the hydrostatlc pressure P can 6 be neglected compared to the osmotic pressure~ Equation (7) can be 7 simplified to Equation (171 by substituting Equation (12) as follows:
8 rb tb = rO2 ho J dr (17) 11 o 12 Equation (17) resu1ts in Equation (18) and Equation (20) by 13 substituting Equation (19) and Equation (16) as follows:

16 tb ~ . k ~ rb ) (18) 17 rb r 18 r= EQ (19) rO . MC . E (20) 21 b 3.~o.t Mp 1 + E~
22 The zero order delivery rate from the capsule pill system follows 23 the osmotiC bursting of each wall of the pill system wherein delivery 24 of drug by osmosis is given by Equation (21):

26 dm = k .~ , A . S (21) ~ o ~

28 Fon a total mass of drug Mto containing N particles of mass ~0 the 1 31 88~5 ARC 1511 1 total surface area is Ato such that Equation (22) and Equation (23) 2 result in Equation (24) set forth as follows:

Ato = N . 4 ~rO2 (22) Mto = N . 4 ~ rO3 . Pp (23) 8 Ato = 3 . Mto (24) rO . Pp IO The delivery rate given by Equation (21) contains the ratio Alh of 11 area and a wall thickness at the time of bursting. This ratio can be 12 calculated as a function of the original value Ao/ho and the 13 elongation EQ . According to Equation (12) it follows that Equation 14 (25) results~
A = Ao . ho (25 16 -h- h2 18 substituting Equation (12) in Equation (25) yields Equation (26).

A = Ao h2 ho ( rO) (26) 23 r = (E~ + 1) rO ~27) 24 Equation (27) exists according to Equation (19) such that Equation (26) and Equation (27) result in Equation (28):
26 A = Ao (EQ + 1)4 (28) 27 h ho 2~

1 The total release rate of N particles of drug follows from Equation (21) 2 and Equation (28) to yield Equation (29) as follows:

4 dt = k ~O S N . Ao (EQ + 1)4 (29) o 6 Since N . Ao is given by Equation (24), Equation (30) results as 7 ~ollows:

10dt = . o ~ S . 3 - h t~o (EQ + 1)4 (30) 11The drug loading is defined by Equa~ion (31):

L= P (31) 13 Mc followed by substituting Equation (16) in Equation (30), results 1n 16Equation (32) as follows:

19 dmt _ k . ~O . S . Mto (E Q + 1) 92. L (32) rO Pp 21 and for a single particle system, Equation (33) and Equation (34) are 22 presented as follows:

24 dm = k ~O . S . Mp ~ (EQ + 1) . ~ (33) Z6 dm = 37.7 x k ~O . S . rO L (1 + EQ )4 (34) 2~ Control over the bursting time and release rate can then be 1 programmed by selecting drug and osmotic properties, respectively ~O
2 and S, loading L, drug particle sizeJ rO, and the wall composition which 3 defines k, and E~ for the above described system with a wall from 4 which delivery occurs in the extended state at r = rb, the release rate and bursting time are inversely proportional as can be seen by 6 eliminating rO2 between Equation (33) and Equation (20) as shown in 7 Equation (35):

dm = 3 . S , Mp . EQ (1 ~ E Q )3 ~35) 9 dt Pp tb The duration of the zero order rate over tz of such a particle is 11 given by Equation (36) where Z is the zero order rate:

13 tz = '~pz (36) wherein Mpz is the mass delivered at zero order rate given by 16 Equation (37)O

18 Mpz , 1 S ( r )3 (37) which is the same relation for an elementary osmotic pump for which 21 r = rO. The ratio of r/rO from Equation (19) yields Equation (38):
22 r 23 M ll - S ( 1 + EQ ~ (38) z = z From Equation (38) and Equation (33) it follows that:

27 t rO ~Pp - S (1 + EQ )~ (39) Z A
28 9 . L . k ~O . S (1 ~ EQ ) -3~-1 Thus, for mathematically ascertaining the time course from the 2 initial burst to the end of the zero order delivery period, it now is 3 possible to calculate the ratio of tz to tb from Equation (39) and 4 Equation (20), the resultin~ Equation (40):
s 6 Z = 1 ~Pp ~ EQ )3 1 (40) 7 tb 3 S (1 + EQ )3 . EQ

8 wherein Equation (40) holds for the delivery system except for the g conditions EQ = 0 when tb = ' The non-zero order rate of release from the tiny pill systems can 11 be expressed by the equations presented below. Thus, according to 12 this study, beyond the zero order time tz the bursted pills deliver in 13 a manner like an elementary osmotic pump; however, at an extended 14 volume consistent with the burst radius. This non zero order rate can be deseribed in the usual probability declining manner where Z is the 16 zero order rate according to Equatton (41) as follows:
8 [ ~V Z ~ (41) Combining Equation (11) and Equation (19) leads to Equation (42):
21 dm z 2223 ~ [ 1 + S . ~ ~ 2 (42) From Equation (20), Equation (39), Equation (34) and 26 Equation (40) it is evident that the delivery profile of such 27 particles is strongly dependent on the elongation EQ ~ For small 28 values of E~ Y O.S, the zero order time is a small fraction of the 1 bursting time tz/tb = 0.3 for an average drug with a particle density 2 1 g/ml and drug solubility 0.3 g/ml.
3 Thus, each individual pill will mostly have a small amount of its 4 drug delivered at zero order. The design of a pill formulation will, by choice, be composed of a mixture of drug with different membrane 6 compositions to adjust k and the bursting time. In addition to coating 7 loading L and osmotic pressure of the drug formulation as well as pill 8 size are very useful variables to control for several of the weight 9 fractions of the formulation.
The wall permeability k is a function of the water sorption X
11 defined by the fraction of water in the saturated wall. This function 12 is described by Equation (43) to describe the data X = 0.02 to X = 0.5 13 as follows:
14 k = 3.5 X 10 8 exp(19.7 X) (43) k is in units [cm2/hr.atm]
16 From Equation (20) and Equation (43) the aperture bursting time 17 in a tiny pill system up to 24 hours is in the approximate range of 18 elongations of 0.1 to O.S, a drug loading L = 0.1 to 3, osmotic 19 pressures up to 300 atm, the preferred drug particle size is rO =
0.001 to 0.1 cm, with wall permeabilities up to 9 X 10 5 cm2/hr.atm.
21 The expressions also indicate that longer bursting times can be 22 achieved for polymers with higher elongations.

-24 A beneficial drug is administered to an animal host, such as a human at a controlled rate according to the method of administration 26 provided by the invention. The method comprises the steps of: (A) 27 admitting orally into the gastrointestinal tract of a human a delivery 28 system comprising: (1) drug dispensing means comprising: (a) a core of 1 a beneficial drug; and (2) wall means for controlling the release of 2 the beneficial drug from the dispensing means, which wall means sur-3 rounds the core of beneficial drug; and (2) means for delaying the 4 release of the beneficial drug from the drug dispensing means, said means a liquid composition comprising a plurality of the drug dis-6 pensing means; and (B) delivering the beneficial drug by permitting 7 the environment of the gastrointestinal tract to contact and dilute the liquid composition, whereby the drug dispensing means release the g beneficial drug at a controlled rate to the gastrointestinal tract over a prolonged period of time.

12 Another dosage form is provided by coating a drug core compo-13 sition comprising procainamide hydrochloride, lactose and magnesium 14 stearate in a fluid air suspension machine with a composition compri-sing ethyl cellulase in ethanol to surround the drug core with a wall 16 of ethyl cellu10se to yield tiny pills thereof. After the solvent is 17 vacuum stripped from the tiny pills~ the pills are blended with a 18 solution comprising sorbitol, propylene glycol, alcohol, water and 19 organe oil.
It will be appreciated by those versed in the art the present 21 invention makes available novel and useful delivery system for dispen-22 sing a beneficial drug over a prolonged period of time. Also, it will 23 be understood by those knowledged in the dispensing art that many 24 embodiments of this invention can be made without departing from the spirit and scope of the invention, and the invention is not to be 26 construed as limited, as it embraces all equivalents therein.

2~

Claims (35)

1. A delivery system for the controlled delivery of a beneficial drug to an environment of use, the delivery system comprising:
(A) a beneficial drug dispensing means comprising:
(1) a composition comprising a beneficial drug; and, (2) wall means for controlling the release of the beneficial drug from the dispensing means, which wall means surrounds the composition;
(B) carrier means comprising a pharmaceutically acceptable liquid for housing a plurality of the beneficial drug dispensing means;
and, (1) means in the carrier for delaying the release of the beneficial drug from the drug dispensing means.

2. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the means for delaying the release of drug retards the release of drug.

3. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the wall means is erodible.

4. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the wall means is permeable to the passage of drug by the process of diffusion.

5. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the wall means is porous.

6. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the wall means forms at least one passageway by bursting in the wall.

7. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the wall means releases a drug by metabolism of the wall in a biological environment.

8. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the beneficial drug dispensing means comprise a plurality of tiny pills.

9. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the pharmaceutically acceptable liquid initially exhibits a concentration equal to the concentration of drug in the drug dispensing means.

10. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the pharmaceutically acceptable liquid exhibits an osmotic pressure substantially equal to the osmotic pressure exhibited by the drug dispensing means.

11. The delivery system for the controlled delivery of a beneficial drug according to claim 1, wherein the beneficial drug dispensing means comprises tiny timed pills and the liquid carrier comprises means for maintaining the physical and chemical integrity of the tiny timed pills while they are in the liquid carrier.

12. A delivery system for the controlled delivery of a beneficial drug to an animal, the delivery system comprising (a) a tiny pill comprising:
(1) a composition comprising a beneficial drug, and (2) a wall comprising a composition for controlling the release of the beneficial drug from the tiny pill, which wall surrounds the composition comprising the beneficial drug;
(b) a carrier comprising a pharmaceutically acceptable liquid;
(3) a plurality of tiny pills in the carrier; and, (4) means in the carrier for delaying the release of the beneficial drug from the tiny pills.

13. The delivery system for the controlled delivery of the drug according to claim 12, wherein the pharmaceutically acceptable liquid comprises a member selected from the group consisting of a water, organic liquid or mixture thereof.

14. A delivery system for the controlled delivery of a beneficial drug to an animal, the delivery system comprising:
(a) a tiny pill comprising, (1) a composition comprising a beneficial drug; and (2) a wall for controlling the release of the beneficial drug from the tiny pill, the wall surrounding the beneficial drug and comprising a semipermeable composition permeable to the passage of fluid;
(b) a carrier comprising a pharmaceutically acceptable liquid;
(3) a plurality of tiny pills in the carrier; and, (4) means in the carrier for retarding the release of beneficial drug for the tiny pills.

15. The delivery system for the controlled delivery of the drug according to claim 14, wherein the liquid comprises a member selected from the group consisting of a water, organic liquid or mixture thereof.

16. A delivery system for the controlled delivery of a beneficial drug to a biological environment of use, the delivery system comprising:
(a) a tiny pill comprising:
(1) a dosage unit amount of a beneficial drug; and, (2) a wall for controlling the release of the beneficial drug from the tiny pill, which wall surrounds the beneficial drug and comprises an erodible composition that erodes in the environment of use;
(b) a pharmaceutically acceptable liquid carrier for housing a plurality of the tiny pills, which carrier comprises;
(3) a plurality of tiny pills in the liquid carrier;
and, (4) means for slowing the erosion of the erodible wall during storage of the tiny pill in the liquid carrier.

17. The delivery system for the controlled delivery of the drug according to claim 16, wherein the liquid comprises a water, organic liquid or mixture thereof comprising a liquid and a solid.

18. A delivery system for the controlled delivery of a beneficial drug to an animal, the delivery system comprising;
(a) a tiny pill, said tiny pill comprising:
(1) a beneficial drug; and, (2) a wall that surrounds the beneficial drug, the wall comprising a release rate controlling composition permeable to the passage of drug by the process of diffusion for administering the drug from the tiny pill;
(b) a pharmaceutically acceptable liquid carrier comprising a plurality of the tiny pills; and, (3) means in the liquid carrier for substantially decreasing passage of drug through the wall of the tiny pills thereby substantially preventing a premature release of drug before the tiny pills are delivered to the animal.

19. The delivery system for the controlled delivery of the drug according to claim 18, wherein the liquid is a member selected from the group consisting of a water, organic liquid or mixture thereof.

20. A delivery system for the controlled delivery of a beneficial drug to an animal, the delivery system comprising:
(a) a tiny pill, comprising:
(1) a beneficial drug; and, (2) a wall comprising pores, which wall surrounds the beneficial drug, which walls releases the drug at a controlled rate by passage through the pores;

(b) a nontoxic liquid carrier comprising a multiplicity of the tiny pills; and, (3) means in the carrier for substantially decreasing the passage of drug through the pores of the wall of the tiny pills.

21. The delivery system for the controlled delivery of the drug according to claim 20, wherein the liquid carrier is a member selected from the group consisting of a water, organic liquid or mixture thereof.

22. A delivery system for the controlled delivery of a beneficial drug to an animal, the delivery system comprising:
(a) a tiny pill comprising:
(1) a beneficial drug; and, (2) a wall that surrounds the beneficial drug, the wall comprising a composition that releases the drug by bursting a passageway in the wall, when the delivery system is in operation in the animal;
(b) carrier means comprising a pharmaceutically acceptable liquid for housing a multiplicity of the tiny pills;
(3) a multiplicity of tiny pills in the carrier; and, (4) means in the liquid for substantially preventing bursting of the passageway in the wall of the tiny pills during a storage period of the tiny pills.

23. The delivery system for the controlled delivery of the drug according to claim 22, wherein the liquid is a member selected from the group consisting of an aqueous media, emulsion, suspension, a liquid comprising a semisolid, elixir, syrup, juice, viscous solution, hydrogel solution, suspension in water media, and semisolid comprising a liquid and a solid.

24. A delivery system for the controlled delivery of a beneficial drug to an animal, the delivery system comprising:
(a) a plurality of tiny pills comprising:
(1) a beneficial drug; and, (2) a wall that surrounds the beneficial drug, the wall comprising a composition that releases the drug by metabolism of the wall, when the tiny pill is in operation in the animal;
(b) a biologically acceptable liquid carrier comprising a multiplicity of the tiny pills; and, (3) means in the liquid for substantially maintaining the physical and chemical integrity of the wall of the tiny pills during the period of time the delivery system is in storage.

25. The delivery system for the controlled delivery of a beneficial drug according to claim 24, wherein the carrier is a member selected from the group consisting of a water, organic liquid and a solid thereof.

26. A delivery system for administering a drug to a warm-blooded animal, wherein the delivery system comprises:

(a) a plurality of tiny pills, which tiny pills comprise;
(1) a therapeutically effective amount of a drug;
(2) a wall that surrounds the drug, which wall comprises a drug release rate controlling composition; and (b) a pharmaceutically acceptable liquid carrier (3) a plurality of tiny pills in the carrier; and, (4) a pharmaceutically acceptable agent in the carrier, which agent exhibits a concentration substantially equal to the concentration of drug in the tiny pill for delaying the release of drug from the tiny pills.

27. A delivery system for administering a drug to an animal, wherein the delivery system comprises:
(a) a plurality of tiny timed pills, which pills comprise:
(1) a therapeutically effective amount of drug;
(2) a wall that surrounds the drug and comprises a composition permeable to the passage of fluid; and, (b) a pharmaceutically acceptable liquid carrier comprising the tiny pills, said carrier exhibiting an osmotic pressure substantially equal to the osmotic pressure exhibited by the drug in the tiny pills.

28. An improvement in a delivery system adapted and designed for administering a drug to a biological recipient, said delivery system comprising;
(a) a plurality of tiny pills, which pills comprise;
(1) a therapeutically effective amount of drug;

(2) a wall that surrounds the drug and comprises an erodible composition; and, (3) a pharmaceutically acceptable carrier comprising a liquid and a plurality of the tiny pills; and wherein the improvement comprises;
(b) means in the carrier for delaying erosion of the wall during storage of the tiny pills in the carrier.

29. An improvement for administering orally a plurality of tiny pills to an animal, wherein the tiny pills comprise;
(a) a therapeutically effective amount of an orally administrable drug; and, (b) a wall that surrounds the drug, the wall comprising a composition permeable to the passage of drug according to Fick's Law of Diffusion; and, wherein the improvement comprises;
(c) a pharmaceutically acceptable liquid carrier comprising the tiny pills, which carrier (1) comprises means for substantially delaying the diffusion of the drug through the wall during storage of the tiny pills, and wherein when the tiny pills are administered to an animal, and (2) is a vehicle for their oral administration.

30. A delivery system for administering a drug to an animal, wherein the delivery system comprises:
(a) a plurality of tiny pills, which pills comprise, (1) a therapeutically effective amount of drug; and (2) a wall that surrounds the drug;

(3) a composition comprising a pore former;
(b) a pharmaceutically acceptable liquid carrier comprising the tiny pills, which carrier comprises means for substantially delaying removal of the pore former from the wall during storage of the delivery system.

31. An improvement for storing tiny pills in a pharmaceutically acceptable liquid, wherein the tiny pills comprise;
(a) a dosage unit amount of drug; and, (b) a wall that surrounds the drug, the wall comprising a composition comprising means for bursting the wall for releasing the drug from the tiny pills and, wherein the improvement comprises;
(c) a pharmaceutically acceptable liquid carrier comprising the tiny pills, which carrier comprises means for substantially delaying bursting in the wall of tiny pills prior to administering the tiny pills to an animal.

32. Use of a delivery system according to any one of claim 1 to 27 and 30 to deliver a beneficial drug to an environment of use in a mammal.

33. Use of an improvement in a delivery system according to claim 28 to deliver a beneficial drug to an environment of use in a mammal.

34. Use of tiny pills according to claim 29 to deliver a beneficial drug to an environment of use in a mammal.

35. Use of an improvement for storing tiny pills according to claim 31 to deliver a beneficial drug to an environment of use in a mammal.