IES930594A2 - Combined drug delivery system - Google Patents

Abstract

A unit dosage formulation of two drugs with different physicochemical properties for oral administration comprises in 5 combination an adsorbate of a first drug and a multi-particulate form of a second drug. The adsorbate and the multi-particulate form, suitably sustained release beads, are combined in a manner in which the respective phases are in contact with each other and whereby the release and absorption characteristics of the respective drugs are 10 maintained over the dosage interval. Typically one of the drugs is water insoluble or unstable in the crystalline state and the other drug is water soluble.

Description

This invention relates to a drug delivery system for the delivery of at least two drugs with different physicochemical properties in a single unit dosage form.

Drugs with different physicochemical properties would normally preclude a combination of the drugs in a single unit dosage form that provides for prolonged release of the drugs over a dosage interval and/or enhanced absorption of the or each drug.

In cases where it is necessary to combine a water soluble drug and a water insoluble drug in a prolonged release control delivery product, it is not possible to use the same means to prolong and maintain the absorption phase of both drugs from a single dosage unit. In such instances, if one were to make use of a system that achieves prolonged release of the water soluble component, this would ensure that application of the same system to the water insoluble component would result in the water insoluble component being unavailable for absorption resulting in a delivery system failure.

In the situation where two drug components are physically incompatible with each other, such incompatible drugs are not suitable for co-incorporation into a single unit dosage form. This is especially the case where it is desired to administer the incompatible drugs in a prolonged release dosage form.

There is thus a need for drug formulations in which drugs with different physicochemical properties can be combined in single unit dosage forms, especially those which ensure prolonged, controlled release and/or enhanced absorption, resulting in greatly increased patient compliance and thus more effective therapy and patient management.

Accordingly, the invention provides a unit dosage formulation of two drugs with different physicochemical properties for oral ^93 0 5 9 4 administration, comprising in combination an adsorbate of a first drug and a multi-particulate form of a second drug, the adsorbate and the multi-particulate form being combined in a manner in which the respective phases are in contact with each other and whereby the release and absorption characteristics of the respective drugs are maintained over the dosage interval.

Normally, the formulation according to the invention will contain two drugs. However, it will be appreciated that more than two drugs can be accommodated in the unit dosage formulation according to the invention.

'Hie formulation according to the invention can be used to incorporate two or more drug compounds into a single unit dosage form in a manner which allows one to achieve prolonged release of the respective drugs and/or enhanced absorption over a dosage interval. Alternatively, one can achieve immediate release of a first drug and prolonged release of a second drug.

According to a first embodiment of the invention, the adsorbate and/or the multi-particulate form is in the form of a tablet.

According to a second embodiment of the invention, the adsorbate and/or the multi-particulate form is dispersed in an erodible gel matrix.

According to a third embodiment of the invention, one phase forms a central core and the other phase is disposed about said central core.

One of the drugs to be administered in the formulation according to the invention is typically water insoluble or unstable in the crystalline state.

Accordingly, a poorly water soluble drug is suitably formulated in an amorphous form as an adsorbate of a mixture of one part by 930594 weight of a drug and from 0.1 to 10 parts by weight of an inert polymer adsorbed on a cross-linked polymer in a ratio of one part by weight of said mixture to 0.5 to 20 parts by weight of the cross-linked polymer.

The existence of the drug in the pore spaces of the cross-linked polymer can be confirmed by X-ray diffraction studies. In the case of certain water-insoluble drugs, the formation of the adsorbate results in an amorphous state which can be verified by X-ray diffraction and, in addition, by differential scanning calorimetry.

The inert polymer is preferably present in the adsorbate in an amount of 0.5 to 3 parts by weight relative to 1 part by weight of the drug. Furthermore, the formulation preferably contains 1 part by weight of the mixture relative to 1 to 10 parts by weight of the crosslinked polymer.

The adsorbate can be formed by dissolving the drug and the inert polymer in a common solvent, mixing the solution thereby obtained with a given quantity of the cross-linked polymer so as to permit adsorption of said drug and said inert polymer to said cross-linked polymer and removing the solvent.

The solvent used is any pharmaceutically suitable co-solvent for the drug and the inert polymer.

The solvent is suitably selected from water, alcohols, ketones, halogenated aliphatic compounds, halogenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof.

Especially preferred solvents include water, hexane, heptane, methanol, ethanol, isopropyl alcohol, acetone, methylethyl ketone, methylisobutyl ketone, methylene chloride, chloroform, carbon tetrachloride, toluene, xylene and tetrahydrofuran. *030594 The inert polymer is suitably polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alkylcelluloses such as methyl- and ethylcellulose, Shellac, polymers sold under the trademark Eudragit, polyethylene glycol, sodium alginate, galactomannone or carboxypolymethylene or mixtures thereof.

A particularly preferred inert polymer is polyvinylpyrrolidone. The greater the viscosity of the polyvinylpyrrolidone used, the slower the release of the drug.

Eudragit polymers are polymeric lacquer substances based on acrylates and/or methacrylates.

Especially suitable Eudragits for use as the inert polymer in the system according to the invention include co-polymers of acrylic and methacrylic acid esters of varying permeability to the drug and aqueous media.

An especially preferred cross-linked polymer is cross-povidone (Polplasdone XL (GAP), Kollidon CL (BASF); Polplasdone XL and Kollidon CL are Trade Marks). Other preferred cross-linked polymers include cross-linked carboxymethylcellulose and cross-linked methylcellulose.

Any drug is suitable for use as active ingredient in the formulation according to the present invention if it is required to be administered in the circumstances outlined above. Some examples are given in Examples 1-4.

Although an adsorbate is preferably used in accordance with the invention with a water-insoluble drug, appropriate selection of the inert polymeric material can be used to formulate a water soluble drug for a particular application. For example, water insoluble, polymeric materials can be used in conjunction with highly water-soluble active drugs to delay the release thereof. -9}059λ The adsorbate can also be blended with a polymer or a mixture of polymers which gel in the presence of water, the amount of the polymer or polymers being effective to produce a desired sustained release effect. Normally such blending is preceded by granulation of the adsorbate. Suitable such polymers include both water soluble and water insoluble polymers including the inert polymers described above An especially suitable group of polymers are the polymers sold under the Trade Mark Methocel.

A water soluble drug for administration in a formulation according to the invention is suitably formulated in a multi-particulate bead or pellet form, hereinafter referred to collectively as beads.

The beads suitably comprise a core of the water soluble drug or a pharmaceutically acceptable salt thereof, where appropriate, and optionally one or more ingredients selected from an organic acid, an organic base and a lubricant and a multi-layer membrane surrounding the core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water soluble polymer, the number of layers in the membrane and the ratio of the water soluble to water insoluble polymer being effective to permit release of the drug from the bead at a rate allowing controlled absorption thereof at therapeutically effective blood levels over a period of not less than 12 hours, following each oral administration.

The multi-particulate form of the drug may include a combination of prolonged release beads as hereinbefore described and rapid release beads, if it is desired to ensure prompt achievement of therapeutically effective blood levels together with prolonged effects.

The rapid release beads are suitably cores without the aforementioned multi-layer membrane.

Suitably, the core comprises the drug or a pharmaceutically acceptable salt thereof and any additional ingredient(s) embedded in a polymeric material in a manner known per se.

The term water soluble polymer as used herein includes polymers which are freely permeable to water, whilst the term water insoluble polymer as used herein includes polymers which are slightly permeable to water.

The polymeric material preferably consists solely of a water insoluble polymer or a polymer which is slightly permeable to water and aqueous solutions of the drug. Alternatively, the polymeric material may consist solely of a water soluble polymer or a polymer which is freely permeable to aqueous solutions of the drug and water. The polymeric material of the core may include a combination of a water insoluble polymer with a water soluble polymer. The ratio of water soluble/freely permeable to water insoluble/slightly permeable polymer is determined by the particular combination of polymers selected.

The water soluble polymer is suitably polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, agar, carrageenan, xanthan, hydroxypropylmethylcellulose or polyethylene glycol or a mixture thereof. An especially preferred water soluble polymer is polyvinylpyrrolidone.

A suitable polymer which is freely permeable to drug and water is a polymer sold under the Trade Mark EUDRAGIT RL.

Tlie water insoluble polymer of the core is suitably ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly (isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate), ^930594 poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) or polyurethane or a mixture thereof.

The water insoluble polymer of the core may also comprise naturally occurring polymers or resins. Especially suitable water insoluble, naturally occurring polymers include Shellac, chitosan, gum juniper or a mixture thereof.

A suitable polymer which is slightly permeable to the drug and water is a polymer sold under the Trade Mark EUDRAGIT RS or a polymer whose permeability is pH dependent and sold under the Trade Mark EUDRAGIT L, EUDRAGIT S or EUDRAGIT E. Especially preferred polymers in this category are EUDRAGIT L.

As indicated above, EUDRAGIT polymers are polymeric lacquer substances based on acrylates and/or methacrylates. The polymeric materials sold under the Trade Mark EUDRAGIT RL and EUDRAGIT RS are acrylic resins comprising copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups and are described in the EUDRAGIT brochure of Messrs. Rohm Pharma GmbH (1985) wherein detailed physical-chemical data of these products is given. The ammonium groups are present as salts and give rise to the permeability of the lacquer films. EUDRAGIT RL and RS are freely permeable (RL) or slightly permeable (RS), respectively, independent of pH.

EUDRAGIT L is an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester. It is insoluble in acids and pure water, It becomes soluble in a neutral to weakly alkaline milieu by forming salts with alkalis. The permeability of EUDRAGIT L is pH dependent. Above pH 5.0, the polymer becomes increasingly permeable. EUDRAGIT L is described in the EUDRAGIT L brochure of Messrs. Rohm Pharma GmbH (1986) wherein detailed physical-chemical data of the product is given. ί 0 5 9 4 The core suitably has a number of layers of the core-forming materials and is built up in a manner known per se.

A multi-layer arrangement of the drug, additional ingredient(s), if any, and polymeric material is preferably built up on a central active core. The active core is formed by blending the drug, additional ingredient(s), if any, and the polymeric material to form a homogenous powder. A portion of the above blend is shaped to form a central core. A multi-layer arrangement is then built up by a successive layering and binding process wherein the remainder of the blend and a polymer binding solution are applied to the active core in alternative layers in a conventional coating pan. Alternatively, an automatic coating system may be used where the remainder of the blend and polymer binding solution is applied to the active core, simultaneously. Conventional automated coating systems include, for example, a CF granulator or a Glatt fluidized bed. The cores are formed to assure a uniform distribution of the drug and excipient ingredients throughout the core. The preferred average diameter of the completed cores is in the range of 0.4 - 1.6 mm, an especially preferred average diameter being in the range of 0.6 - 1.2 mm.

The multi-layer arrangement of the drug, additional ingredient(s), if any, and polymeric material may also be built up on a central inert core, suitably consisting of a non-pareil bead or seed of sugar/starch having an average diameter in the range 0.2-1.4 mm, especially 0.3-0.8 mm. The drug, additional ingredient(s) and polymeric material may be built up on a central inert core as hereinbefore defined in a conventional coating pan or any automated coating system.

The drug and optional other components are blended to form a homogenous powder. Ihe drug component and organic acid or organic base, if present, are preferably present in a ratio of from 20:1 to 1: 2, more especially 6:1 to 1:1. Ihe blend is suitably passed through the appropriate mesh screen using a milling machine. In the case of coating in a conventional coating pan, alternate layers of a coating solution/suspension of the polymeric material and the powder are applied to the central inert core to build up the multi-layer arrangement of the core. In the case of an automatic coating system, the coating solution/suspension of the polymeric material and the powder are applied, simultaneously, in conventional manner. The coating solution/suspension of the polymeric material comprises one or more polymers dissolved/suspended in a suitable solvent or mixture of solvents. The concentration of the polymeric material in the coating solution/suspension is determined by the viscosity of the final solution/suspension. Preferably, between 5 and 60 parts of the central inert cores are used relative to the homogenous powder. The addition of a plasticizing agent to the polymeric solution/suspension may be necessary depending on the formulation to improve the elasticity and also the stability of the polymer film and to prevent changes in the polymer permeability over prolonged storage. Such changes could affect the drug release rate. Suitable plasticizing agents include polyethylene glycol, propylene glycol, glycerol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and varying percentages of acetylated monoglycerides.

As mentioned above, the core may optionally contain a lubricant. A preferred range of drug to lubricant ratio when a central inert core is used is 50.1 to 5:1.

Preferred coating materials include - solutions/suspensions of the polymers cited for use in the application of the powder blend to the central cores in a suitable organic/aqueous earner medium.

The membrane of the film-forming polymer or mixture of polymers surrounding the core preferably has a proportion of a polymer which is slightly permeable to the drug and water and optionally a proportion of a water permeable polymer, the ratio of water slightly permeable to water permeable polymer being determined by the inherent permeability characteristics of the polymer(s) selected. 930504 ίο The membrane may also be composed of a proportion of a polymer which is water insoluble and a proportion of a polymer which is water soluble, the ratio of water insoluble to water soluble polymer being determined by the inherent permeability characteristics of the respective polymers.

Normally the ratio of water insoluble/slightly permeable polymers to water soluble/permeable polymers lies between 1:5 and 50:1, more usually 1:2 and 20:1. Examples of each of these types of polymer are described above. Especially useful water soluble/permeable polymers include polyvinylpyrrolidone, polyvinyl alcohol and EUDRAGIT RL, whilst useful water insoluble/slightly permeable polymers include ethylcellulose, cellulose acetate, EUDRAGIT RS, EUDRAGIT L, EUDRAGIT E and EUDRAGIT S. Commercially available ready-made polymeric solutions/suspensions may also be useful. These ready-made solutions/suspensions may optionally contain plasticizing agents to improve the polymer film as described previously. Examples of ready-made solutions/suspensions of polymeric material with or without plasticizing agent include EUDRAGIT RL 30D, EUDRAGIT NE 30D, EUDRAGIT E 12.5, EUDRAGIT L 12.5 P, EUDRAGIT E 12.5, EUDRAGIT S 12.5 P, EUDRAGIT RL 12.5, EUDRAGIT RS 300, EUDRAGIT RS 12.5, AQUACOAT (a Trade Mark of FMC Corporation) and SURE-LEASE (a Trade Mark of Colorcon Inc.).

The water insoluble polymer of the membrane may also comprise naturally occurring polymers or resins. Especially suitable water insoluble, naturally occurring polymers include Shellac, chitosan, gum juniper or a mixture thereof. l he membrane may be built up by applying a plurality of coats of membrane polymer solution or suspension to the core as hereinafter described. The membrane solution or suspension contains the polymer(s) dissolved or suspended, respectively, in a suitable aqueous or organic solvent or mixture of solvents, optionally in the presence of a lubricant. Suitable lubricants are talc, stearic acid, magnesium 930594 stearate and sodium stearate. A particularly preferred lubricant is talc. The membrane, polymer or mixture of polymers may optionally include a plasticizing agent, the function and choice of which has been previously described.

The dissolution rate achieved is proportionally slower as the amount of membrane applied is increased.

The membrane solution or suspension may be applied to the active cores in a conventional coating pan as indicated or, alternatively, using an automated system such as a CF granulator, for example, a FREUND CF granulator, a GLATT fluidized bed processor, an AEROMAT1C, a modified ACCELA-COTA or any other suitably automated bead coating equipment (FREUND, GLATT, AEROMATIC and ACCELA-COTA are all Trade Marks).

Preferably 2-75 ml of membrane solution/suspension is applied per application per kilogram of cores. In an automated system the total amount of membrane solution/suspension applied to the cores is the same as that applied in a conventional coating pan, except that the membrane solution/suspension may be applied continuously.

Preferably, when a coating pan is used the membrane is applied at a rate of 5-30 applications/day until all of the applications have been applied. Between days the pellets are dried for a suitable period of time at a controlled temperature.

The two drug components formulated as an adsorbate and as beads, respectively, can be combined in a variety of ways to achieve a combined drug delivery system in a single unit dosage form. Such combinations can be achieved in various ways, but suitably as follows: i) Beads of the water soluble drug are tabletted with an amorphous mixture of a water insoluble drug as an adsorbate in a form that provides for immediate release of the beads from the tablet after ingestion. Ihe beads can be of a type as 930594. hereinbefore described that results in there being prolonged release of water soluble drug coupled with rapid dissolution of water insoluble drug and rapid onset of action. ii) An adsorbate of water insoluble drug is formed and tabletted in the manner hereinabove described. The tablet so formed is of a size (for example 6 mm in diameter) that is compatible with its being filled into a standard pharmaceutical capsule into which beads of a water soluble drug are additionally loaded. This capsule presentation is formulated so that it provides in a single unit dosage form the controlled release of both a water soluble drug and a water insoluble drug. iii) A water soluble drug formulated as controlled release beads as hereinabove described and an adsorbate of a water insoluble drug in an erodible gel matrix are tabletted allowing for erosion and controlled release of the respective drugs of the dosage form over a prolonged period. iv) A tablet presentation comprising an inner core of an adsorbate of a water insoluble drug in an erodible gel matrix surrounded by an outer layer of controlled release beads containing a water soluble drug, said outer layer optionally containing some immediately available water insoluble drug in an amorphous state.

The erodible gel matrix which is a feature of formulation types iii) and iv) is formed by a polymer or mixture of polymers which gel(s) in the presence of water. Suitable such polymers are indicated above. In the case of an adsorbate, the adsorbate is suitably granulated prior to blending with such a polymer or mixture of polymers. When required, as in the case of formulation type iii), beads and granulated adsorbate are blended with the polymer or mixture of polymers to form an erodible gel matrix with the beads and adsorbate granules distributed uniformly therein. $30594 As regards a type iv) formulation, the inner core comprises a tablet formed from a granulated adsorbate blended with a polymer or mixture of polymers which gel(s) in the presence of water and tabletted in a manner known per se. The latter tablet (~5 mm in diameter) forms the core of a larger tablet (~10 mm in diameter), the outer layer of which contains controlled release beads. The formation of such tablets is carried out in a manner known per se.

The invention will be further illustrated by the following Examples.

Example 1 Terfenadine/pseudoephedrine hydrochloride Terfenadine, a water insoluble antihistamine, is formulated in an amorphous state as follows: 1 kg terfenadine is dissolved in 50 kg of acetone to which is added 0.5 kg of polyvinylpyrrolidone. The resulting solution is then mixed with 2.5 kg of cross-linked polyvinylpyrrolidone and the solvent is evaporated. The resulting adsorbate is dried and milled to a pharmaceutically acceptable size.

Pseudoephedrine hydrochloride is formulated as follows: 1 kg of pseudoephedrine hydrochloride and 0.1 kg fumaric acid are blended and milled to a pharmaceutically acceptable size. The resulting powder is applied on to an inert starch sugar core using polyvinylpyrrolidone as a binder. Subsequently the particles are sprayed with a rate controlling polymer such as an Ethocel (Ethocel is a Trade Mark) /polyvinylpyrrolidone mixture in a ratio of 9:1 in the manner hereinabove described until the desired dissolution profile is obtained. The resulting beads provide for prolonged release of pseudoephedrine over 24 hours.

The pseudoephedrine component and the terfenadine component are compressed into a tablet dosage form in the ratio of 240 mg pseudoephedrine to 120 mg terfenadine and sufficient Avicel (Avicel is 930594 a Trade Mark) and magnesium stearate to allow for ease of compressibility.

The resulting tablet product provides a dosage form that achieves 24 hour release of pseudoephedrine and immediate availability of the terfenadine component. The pseudoephedrine drug in a nonformulated standard state normally is taken four to six times a day whereas terfenadine is normally required to be taken only once or twice a day.

Example 2 Nifedipine/propranolol kg of nifedipine is dissolved in 10 kg of methylene chloride.

To this solution is added 0.5 kg of polyvinylpyrrolidone which is further dissolved. 3 kg of cross-linked of polyvinylpyrrolidone is added to this solution and the drug polymer solution is adsorbed on to the surface of the cross-linked polyvinylpyrrolidone. The excess solvent is removed and the resulting adsorbate is granulated and milled. The adsorbate is compressed into tablets with the aid of magnesium stearate, microcrystaliine cellulose and sodium alginate at percentages of 50%, 0.5%, 20% and 29.5%, respectively. The resulting product is compressed into tablets 6 mm in diameter containing 10 mg of nifedipine. kg of propranolol is blended with 250 g of fumaric acid and milled. The drug acid mixture is applied on to inert sugar cores with a polyvinylpyrrolidone polymer solution. The resulting cores are coated with a Eudragit based polymeric system to retard the dissolution rate in the manner described in EP-A 0 123 470.

The propranolol multi-particulate product is encapsulated into size double zero capsules at doses ranging from 80 to 160 mg. In addition to filling the multi-particulate delivery system into the capsule, a dose of nifedipine adsorbate manufactured in the manner described 3 0 5 9 4 above is added to the capsule in doses ranging from 10 to 30 mg. The resulting products provide for a once-daily delivery of propranolol and nifedipine in a single unit dosage form.

Example 3 Diclofenac sodium/naproxen Kg diclofenac sodium is dissolved in a suitably chosen organic solvent to which is added 0.5 kg of polyvinylpyrrolidone. The resulting solution is adsorbed on to 2 kg of cross-linked polyvinylpyrrolidone. The adsorbate is tabletted into a tablet with magnesium stearate, colloidal silica and hydroxypropylmethylcellulose at a ratio of 50:0.5:10:39.5, respectively. The resulting tablet is coated with Eudragit S in a manner to prevent release of drug in the gastric milieu. This tablet is then tabletted with an outer core comprising sodium naproxen in an immediately available mu Iti-particulate state as described in EP-A-0 438 249. The resulting product has the advantage of immediate onset of action through the quickly available sodium naproxen, as well as the delayed onset of action, once it has passed through the stomach, of the diclofenac sodium component. This allows for the unique delivery of two potentially incompatible nonsteroidal anti-inflammatory agents.

Example 4 Aspirin/nifedipine Aspirin is applied on to inert sugar cores and coated with an Ethocel (Ethocel is a Trade Mark)/polyvinylpyrrolidone mixture in the manner described above to provide for long acting controlled release delivery of aspirin over a 24 hour interval. The resulting multiparticulate delivery system is combined with a nifedipine adsorbate erodible gel matrix tablet, as described in Example 2. The resulting product then provides for a gel matrix which delivers nifedipine over a 24 hour interval and 24 hour delivery of aspirin through erosion of the 930594 matrix and subsequent release of the multi-particulate system and delivery absorption of drug.

This invention is not limited to the embodiments described above 5 which may be modified and/or varied without departing from the scope of the invention.

Claims (5)

Claims:

1. A unit dosage formulation of two drugs with different physicochemical properties for oral administration, comprising in combination an adsorbate of a first drug and a multi-particulate form 5 of a second drug, the adsorbate and the multi-particulate form being combined in a manner in which the respective phases are in contact with each other and whereby the release and absorption characteristics of the respective drugs are maintained over the dosage interval.

2. A unit dosage formulation according to Claim 1, wherein 10 the adsorbate and/or the multi-particulate form is in the form of a tablet.

3. A unit dosage formulation according to Claim 1, wherein the adsorbate and/or the multi-particulate form is dispersed in an erodible gel matrix. 15

4. A unit dosage formulation according to Claim 1 or 3, wherein one phase forms a central core and the other phase is disposed about said central core.

5. A unit dosage formulation according to Claim 1, substantially as hereinbefore described and exemplified.