Method for adminstering tiny pills

Another object of the present invention is to provide a delivery system housing tiny pills for dispensing two drugs essentially free of chemical interaction attributed to chemical incompatibility, thereby overcoming the problems associated with the prior art. 5

Another object of the invention is to provide a delivery system comprising tiny pills in a fluidic vehicle, and whereing the tiny pills exhibit prolonged storage and shelf life.

These objects as well as other objects, features and 10 advantages of the invention will become more apparent from the following detailed description of the invention, the drawings and the accompanying claims.

In the drawings, which are not drawn to scale but are set forth to illustrate various embodiments of the invention, the drawing figures as as follows:

FIG. 1 depicts a container that can be used for containing the delivery systems provided by the invention; 20

FIG. 2 is an opened view of a container for depicting a delivery system provided by the invention, which delivery system comprises tiny pills in a fluid medium;

FIG. 3 is similar to FIG. 2 wherein FIG. 3 illustrates tiny pills that release a beneficial drug by an osmotic 25 process;

FIG. 4 is a view of a delivery system comprising tiny pills in a fluid which tiny pills release a drug by controlled disintegration;

FIG. 5 is a view of a delivery system comprising tiny 30 pills in a fluidic means which tiny pills deliver a beneficial drug by the process of diffusion;

FIG. 6 is a view of a delivery system comprising tiny pills in a fluid environment, which tiny pills release a beneficial drug through a microporous wall; 35

FIG. 7 is a view of a delivery system comprising tiny pills in a fluicLenvironment, which tiny pills release a beneficial drug by a process of erosion;

FIG. 8 illustrates a container with a pouring member useful for storing and then pouring the delivery system 40 to a spoon, or the like, for administering the delivery system to a patient;

FIG. 9 is a graph depicting the osmotic bursting time for delivery systems provided by the invention;

FIG. 10 is a graph depicting the rate of delivery of 45 drug from osmotic bursting delivery systems;

FIG. 11 depicts the rate of release from an osmotic bursting aperture forming delivery system;

FIG. 12 depicts the effects of deformation on a wall of a delivery system; 50

FIG. 13 depicts the zero order rate of release from a delivery system over time; and,

FIG. 14 is an opened view for illustrating the structure of a delivery system.

In the drawings and specifications, like parts in re- 55 lated drawing figures are identified by 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. 60

DETAILED DESCRIPTION OF THE
DRAWINGS

Turning now to the drawings in detail, which are an example of the various delivery systems provided by 65 the invention, and which example is not to be construed as limiting, one example of a delivery system is seen in FIGS. 1 and 2. In FIG. 1 a container 10 is illustrated for

housing the delivery system provided by the invention. The container can be any receptacle for holding a liquid, and the like, such as a bottle made of glass or plastic, a capsule, cup, beaker, and the like.

In FIG. 2 container 10 of FIG. 1 is seen in openedsection at 11 for illustrating a lumen 12 that houses a delivery system provided by the invention. The delivery system comprises a multiplicity of tiny pills 13. Tiny pills 13 are a first dispensing means for the controlled delivery of a beneficial agent, such as a drug, both immediately and over a prolonged period of time. Tiny pills 13, an agent dispensing means, comprise a core of beneficial agent 14, such as a drug, surrounded by a wall 15 formed of a release rate controlling material. Tiny pills 13 can have a wall 15, in one embodiment, made 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 an enteric composition which prevents release of beneficial agent 14 in the stomach, but will release beneficial agent 14 in the intestine. Additionally, the composition comprising wall 15 can be selected, in presently preferred embodiments, from wall-forming nontoxic compositions that release beneficial agent 14 by different physical-chemical mechanisms. These mechanisms include osmosis, diffusion, erosion, disintegration, metabolism, and like mechanisms. Wall 15 can have various thicknesses as an additional aid for providing immediate timed release and prolonged timed release of beneficial agent 14.

The delivery system provided by the invention comprises also means 16. Means 16, a pharmaceutically acceptable carrier, comprises 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 such as a drug receptor, (c) for governing the release of beneficial agent 14 from the tiny pills 13, and (d) for keeping the shelf life of the tiny pills. Means 16 comprises a nontoxic, inert fluidic carrier such as a member selected from the group consisting of an inorganic liquid, an organic liquid, aqueous media, emulsion, suspension, liquid comprising semisolids, elixir, syrup, juice, osmotic solution, viscous solution, hydrogel solution, gel suspension in a water media, pharmacologically acceptable liquid, semisolid comprising a liquid and a solid, and the like. Means 16, in a presently preferred embodiment, governs and substantially prevents a premature release of beneficial agent 14 from tiny pills 13 into a liquid means 16 in container 10. Means 16 governs the release of beneficial agent 14 by exhibiting an osmotic pressure or a concentration in a liquid means 16 that is substantially equal to, or higher than the osmotic pressure or the concentration gradient exhibited by beneficial agent 14 across wall 15 of tiny pills 13 against liquid means 16. For example, for a beneficial agent 14 exhibiting an osmotic pressure of irt, or for a beneficial agent 14 blended with an osmotically effective solute exhibiting an osmotic pressure of 7Tr, the osmotic pressure exhibited by liquid means 16 is equal to Ttl, or greater than Ttl, such that Ttl^^u where Trt is the osmotic pressure of the tiny pills. This inventive feature provides also means for storing the delivery system essentially-free of drug release during storage.

The osmotic pressure of the concentration of liquid means 16 can be regulated by adding a composition of matter to liquid means 16. The composition of matter can be in any physical form such as powder, particle, crystal, strip, film, granules, fiber, and the like. The composition of matter additionally can comprise a bene5

ficial agent, an osmagent or an osmopolymer. Osmagents are known also as osmotically effective compounds and as osmotically effective solutes. The beneficial agent can be a drug that is the same or different than a drug in a tiny pill. Representative osmagents useful for 5 blending with the liquid include carboxylic acids such as dicarboxylic, tricarboxylic, hydroxydicarboxylic, hydroxytricarboxylic and dihydroxycarboxylic acids such as tartaric, citric, maleic, succinic, fumaric, mixtures thereof, and the like; examples of osmotically 10 active solutes include solutes such as sodium chloride, magnesium sulfate, magnesium chloride, potassium chloride, sodium sulfate, lithium sulfate, potassium acid phosphate and the like; carbohydrates such as raffinose, succrose, glucose, lactose, galactose, altrose, monosac- 15 charides, disaccharides, polysaccharides, mixtures thereof, and the like; examples of alcohols include alcohols such as sorbitol also known as hexanehexol, mannitol and the like; examples of gels include such as gum Arabic, agar, acacia, tragacanth, and the like; Other 20 ingredients that can be added to the liquid include urea, inositol and like osmotic solutes.

The osmotic solute is present in any physical form that is compatible with a host, and with the tiny pills. The osmotic pressure of a solution of variously osmoti- 25 cally active compounds and a solution of a beneficial agent such as a drug used for making tiny pills is measured in a commercially available osmometer that measures the vapor pressure difference between pure water and the solution to be analyzed and, according to stan- 30 dard thermodynamic principles, the vapor pressure ratio is converted into an osmotic pressure difference. An osmometer that can be used for the present measurements is identified as Model 320B, Vapor Pressure Osmometer, manufactured by the Hewlett Packard Co., 35 Avondale, PA. Procedures for measuring osmotic pressure using thermodynamic principles are disclosed in U.S. Pat. Nos. 4,160,020 and 4,576,604.

FIG. 3 is an opened section depicting a delivery system provided by the invention. FIG. 3 illustrates a plu- 40 rality of tiny pills 13 that release a drug by osmotic principles. In FIG. 3, tiny pills 13 comprise a wall 15 that releases a beneficial agent 14 by the process of osmotic bursting over time. In a presently preferred embodiment, beneficial agent 14 is a drug. The drug, in 45 one embodiment, is present in the form of an osmotic solute, such as a therapeutically acceptable salt, that exhibits an osmotic pressure gradient across wall 15 against distilled water, or the drug can be mixed with an osmotically effective solute that exhibits an osmotic 50 pressure gradient across wall 15 against distilled water. In FIG. 3, in the embodiment illustrated, fluidic means 16 comprises a concentration substantially equal to or larger than the concentration of drug 14 in tiny pill 13 thereby providing an initial concentration gradient sub- 55 stantially equal to zero. The wall forming composition used to manufacture wall 15 comprises those materials permeable to the passage of an external fluid present in an environment of use and substantially impermeable to the passage of drug and osmotic solute. Typical materi- 60 als include a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate having a degree of substitution, D.S., up to 1 and an acetyl content of 21%; cellu- 65 lose diacetate having a D.S. of 1 to 2 and an acetyl content of 21% to 35%; cellulose triacetate having a D.S. of 2 to 3 and an acetyl content of 35% to 44.8%;

6

cellulose acetate propionate, cellulose acetate butyrate, ethyl cellulose semipermeable polyurethane, and the like. The osmotic wall can be coated around the drug in varying thicknesses by pan coating, spray-coating, Wurster® fluid air-suspension coating, coacervation techniques, and the like. The wall is applied using organic solvents such as methylene chloride-methanol, methylene chloride-acetone, methanol-acetone, ethylene dichloride-acetone, and the like. Osmotic wall forming materials, and procedures for forming the wall, and osmotic bursting procedures are disclosed in U.S. Pat. Nos. 2,799,241; 3,952,741; 4,014,334 and 4,016,880.

Drug 14, neat, or a combination of drug 14 and osmotically effective solute in pill 13, in one embodiment, will have a particle size of 0.1 to 1000 micron, and a presently preferred particle size of about 0.5 to 300 microns, average. Procedures for measuring the surface area average diameter of agent solutes are reported in J. Am. Chem. Soc, Vol. 6, p 309, (1938); The Surface Chemistry of Solids, by Gregg, 2nd Ed., (1961), published by Remhold Corp., New York; in Absorption, Surface Area and Porosity, by Gregg et al., (1967), published by Academic Press, New York; in Physical Absorption of Gases, by Yound et al., (1962), published by Butterworth and Co., Ltd., London; and in Fine Particle Measurements, by Valla (1959), published by Macmillan Co., New York.

Procedures for ascertaining the impermeability or the permeability of a polymer film used for providing wall 15 of osmotic bursting pill 13 are known to the art in Proc. Roy. Sci., London, Series A, Vol. 148, (1935); J. Pharm. Sci., Vol. 55, pp 1224-29, (1966); in Diffusion in Solids, Liquids and Gases, by Jost, Chapter XI, pp 436-88, (1960), published by Academic Press, Inc., New York. Procedures for measure osmotic bursting aperture formation in a polymeric film by the hydrostatic pressure in the pill exceeding the cohesive integrity of the polymeric film, with the polymer wall 15, can be determined by measurements predicted on pressuredeflection and mechanical behavior measurement techniques reported in Modern Plastics, Vol. 41, pp 143-44, 146 and 186, (1964); Handbook of Common Polymers, by Scott et a., pp 588-609, (1971), published by CRC Press, Cleveland, OH; in Machine Design, pp 107-11, (1975); in /. Sci. Instruments, Vol. 42, pp 591-96, (1965); and by measuring mechanical stress-strain patterns of polymers using the Instron® Testing Machine, available from the Instron Corporation of Canton, MA.

In FIG. 4 another delivery system is seen provided by the invention. In FIG. 4 tiny pills 17 comprise drug 18 surrounded by wall 19 of tiny pill 17 initially present in fluidic means 16. Wall 19 in the illustrated embodiment comprises a composition consisting essentially of a fatty ester mixed with a wax. Representative fatty esters include a member selected from the group consisting of triglyceryl ester, glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodeconate, glyceryl didecenoate, and glyceryl tridecenoate.

The wax, in one representative embodiment, included in the wall forming composition is a member selected from the group consisting essentially of beeswax, cetyl palmitate, spermacetic wax, carnauba wax, cetyl myris