WO2004034959A2

WO2004034959A2 - Multiparticulate modified release composition comprising beraprost

Info

Publication number: WO2004034959A2
Application number: PCT/IB2003/006415
Authority: WO
Inventors: Paul Stark; Theresa Jeary; Fiona Palmer; Jackie Butler; Janet Codd
Original assignee: Elan Corporation, Plc
Priority date: 2002-09-18
Filing date: 2003-09-18
Publication date: 2004-04-29
Also published as: AU2003296852A1; AU2003296852A8; WO2004034959A3

Abstract

A formulation which is capable of being taken orally for the delivery of beraprost sodium and which comprises the following components, each of which includes the beraprost sodium: (A) an instant-release (IR) component which releases substantially all of the beraprost sodium thereof in the stomach within about 15 minutes after ingestion; (B) a sustained-release (SR) component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body over a period of time of about 6 hours after ingestion; and (C) a delayedrelease (DR) component which includes: (i) a sub-component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body in a period of time of about 6 to about 12 hours after ingestion; and (ii) another sub-component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body in a period of time of about 12 to about 18 hours after ingestion, and the use of the formulation in therapeutically effective amounts to treat various types of conditions, for example, peripheral vascular disease, thrombosis, pulmonary ischemia, pulmonary hypertension, diabetes, and neuropathy.

Description

Pharmaceutical Formulation

Related Application

This application is based on and claims priority to U.S. provisional Application No. 60/412,124, filed September 18, 2002.

Field of the Invention

This invention relates to a controlled-release pharmaceutical formulation. More particularly, this invention relates to a controlled-release pharmaceutical formulation which contains beraprost sodium and which is capable of being administered orally.

Beraprost sodium (beraprost) is an analogue of prostacyclin which in turn is a type of prostaglandin of the formula C₂₀H₃₂O₅ Prostaglandins inhibit specifically the formation of blood clots and are a class of unsaturated fatty acids that are involved in the contraction of smooth muscle, the control of inflammation and body temperature, and many other physiological functions; they are any of a group of about a dozen compounds synthesized from fatty acids in mammals as well as in lower animals.

Prostaglandins are highly potent substances that are not stored in the body, but are produced as needed by cell membranes in virtually every body tissue. They are hormone-like. Different prostaglandins have been found to raise or lower blood pressure and regulate smooth muscle activity and glandular secretion.

Prostacyclins are an endogenous-type of prostaglandins synthesized by vascular endothelial cells. Prostacyclins have potent inhibitory effects on platelet adhesion/aggregation and vasoconstriction, but their therapeutic use is restricted by their extremely short half-life. Beraprost is, however, more chemically stable than other prostacyclins; it possesses a phenol moiety instead of the exo-enol ether moiety, which causes the instability of prostacyclins. In addition, beraprost has a modified omega-side chain that contributes to dissociating antiplatelet action from adverse reactions.

Beraprost, which is highly soluble in water, has a variety of biological activities such as antiplatelet effects, vasodilation effects, antiproliferative effects on vascular smooth muscle cells, cytoprotective effects on endothelial cells and inhibitory effects on the production of inflammatory cytokines. On the basis of basic and clinical research, it has been suggested that beraprost is effective also for many intractable diseases.

Beraprost is the first orally active prostacyclin analogue. In 1992, beraprost was approved as a drug for chronic arterial occlusion. Beraprost is now used widely clinically as "Dorner'Or "Procylin". The indication for "primary pulmonary hypertension" was approved also in 1999. Recently in Europe, a placebo controlled trial named "Beraprost er Claudication Intermittent-2 (BERCI-2)" was performed; it was reported that beraprost improved the walking distances of the patients.

There is evidence also that beraprost may be an effective treatment for early- state peripheral vascular disease and for early-stage pulmonary arterial hypertension. Intermittent oral doses of beraprost do not provide, however, consistent levels of the drug in the blood necessary to treat advanced stages of peripheral vascular disease or pulmonary arterial hypertension. The present invention addresses this shortcoming of the state of the prior art respecting beraprost. Summary of the Invention

In accordance with the present invention, there is provided a formulation which is capable of being taken orally for the delivery of beraprost sodium and which comprises the following components, each of which includes the beraprost sodium: (A) an instant-release (IR) component which releases substantially all of the beraprost sodium thereof in the stomach within about 15 minutes after ingestion; (B) a sustained-release (SR) component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body over a period of time of about 6 hours after ingestion; and (C) a delayed-release (DR) component which includes: (i) at least one sub-component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body in a period of time of about 6 to about 12 hours after ingestion; and (ii) at least one other sub-component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body in a period of time of about 12 to about 18 hours after ingestion.

In a preferred embodiment, the present invention provides a daily dosage of the formulation in which the components comprising the formulation are in the form of mini-tablets or multi-particulates, for example, beads contained within a single capsule.

Another aspect of the present invention is the provision of a method for supplying therapeutic amounts of beraprost sodium to serum of an animal, preferably a human, through the animal's gastrointestinal tract by oral ingestion of a therapeutically effective amount of the formulation. The present invention is useful for treating humans to inhibit platelet adhesion/aggregation and vasoconstriction and to exert anti-proliferative effects on vascular smooth muscle cell and to exert cytoprotective effects on endothelial cells and inhibitory effects on the production of inflammatory cytokines. Detailed Description of the Invention

The various components comprising the formulation of the present invention can be in any suitable form, for example, in the form of mini-tablets, beads, and granules, or a mixture of two or more of the aforementioned. As described below, it is preferred that the components of the formulation be in the form of mini-tablets or beads and that the mini-tablets or beads be contained in a capsule which is suitable for oral ingestion by the user. There follows a description of the components comprising the formulation, namely: (A) the instant-release (IR) component; (B) the sustained- release (SR) component; and (C) the delayed-release (DR) component which, as described below, contains a plurality of sub-components.

Instant-Release Component

The instant-release or IR component of the formulation comprises beraprost sodium (hereafter "beraprost") in a form such that the beraprost is released in the stomach promptly after the formulation is ingested, for example, there is an immediate, burst-release of the beraprost, for example, substantially all of the beraprost (over about 90 wt. %) is released within about 15 minutes after ingestion of the IR component.

The IR component comprises the beraprost and a binding agent which binds together the constituents comprising the component. The binding agent is a material which is capable of being dissolved readily by liquids in the stomach to release the beraprost. Examples of binding agents are hydroxypropylcellulose and polyvinyl pyrrodine. Examples of other materials (excipients) that can be used in forming the mini-tablets are: flow-control agents, for example, colloidal silicon dioxide; lubricants, for example, magnesium stearate and stearic acid; fillers, for example, lactose and microcrystalline cellulose; and disintegrants, for example, starch. It should be understood that the mini-tablet can comprise also other materials that do not interfere with the function of the IR component.

The IR component can be made in the form of a mini-tablet in any suitable way to provide a mini-tablet that has a suitable size, for example, about 1 to about 5 mm in diameter. An exemplary way of making the mini-tablet is to mix by high-shear and/or tumbling action a powdered form of beraprost with excipients which include one or more materials which function to bind together the solid particles comprising the mini- tablet. After obtaining a homogeneous mixture of the components, they can be subjected to tableting on a single or rotary tablet press to form the IR mini-tablet.

Another exemplary way of forming the mini-tablet is to prepare a mixture in powdered form of the beraprost and various of the other solid constituents of the mini- tablet by pre-mixing the constituents utilizing high-shear or tumbling action and then combining the resulting mixture with a solution, preferably an aqueous solution, of the binding agent in a fluidized bed or high-shear apparatus to produce a wet mass/extrudate/granulate that can be tabletted, with or without additional excipients, using a single-station or rotary tablet press to produce the IR mini-tablet.

An additional exemplary way of forming the mini-tablet is to prepare a solution, preferably aqueous, of the beraprost and, optionally, the binding agent. The solution can be sprayed onto a dilutent using high-shear/fluid-bed or similar apparatus ^' to produce a substrate which can then be tabletted, with or without additional excipients, to produce the IR mini-tablet. The mini-tablet can be coated optionally according to known techniques with a coating composition that forms a protective coating that dissolves readily in the stomach. Sustained-Release Component

The sustained release or SR component of the formulations comprises beraprost in a form such that the beraprost is released in the body over a period of time of about six hours after ingestion. The SR component includes means to extend the release time of the beraprost, as indicated. Such means can include, for example, the use of a coating which functions to extend the release time of the beraprost or the use in SR component of a matrix which functions to extend the release time of the beraprost.

A preferred SR component comprises a mini-tablet, for example, an IR mini- tablet as described above, that is coated with a material that delays the release of the beraprost from the mini-tablet. Such coating material, typically a polymer, is referred to often as a "control-release material" or "control-release polymer" and has film- forming properties. Such materials are well known and are used in the present invention to impart to the SR component the desired beraprost release profile. Examples of preferred control-release polymers that can be used are ammonio methacrylate copolymers and methacrylic acid copolymers. Coating compositions can be formulated from such individual polymers or in admixture or they can be formulated from such polymer(s) in combination with other polymers, for example, povidines and alkylcellulose, preferably ethylcellulose.

The coating composition, preferably aqueous-based, can include other constituents which function to improve the properties of the control-release coating and/or to aid processing aspects of the coating operation. Examples of such constituents include: anti-adherents, for example, talc, colloidal silicon dioxide, and glyceryl monostearate; plasticisers, for example, dibutyl sebecate (DBS), diethyl phthalate, citric acid esters, polyethylene glycols, and ethylene glycol; and anti- foaming agents, for example, simethicone. Dibutyl sebacate and triethyl citrate are preferred plasticisers. The amount of plasticiser to be used in the coating composition is preferably from about 10% to 50%, most preferably about 20% based on the weight of the dry film-former comprising the composition. The amount of anti-foaming agent to be used in the coating composition is preferably from 0.01% to 0.5% of the coating composition.

The amount of coating composition applied to the mini-tablets will depend on various factors, including, for example, the concentration of the control-release material in the coating composition, the desired release properties for the beraprost, the amount of beraprost to be delivered, and the size of the mini-tablets. The coating composition can be applied to the mini-tablets by any suitable method, including, for example, spraying which is a preferred method. Spraying can be carried out using a fluidised bed coater (preferably using a Wurster system) or in a pan coating system. After application of the coating composition, the wet coating can be dried and/or cured under conditions which are suitable for the particular film-forming constituent that is present in the composition.

Another preferred form of the SR component is a mini-tablet which contains the beraprost associated with a matrix (for example, solids dispersed therein) which comprises a material that delays and gradually extends the time of release of the beraprost from the mini-tablet. Species of such types of materials are known; they impart control-release properties to the mini-tablet. A mixture of such materials can be used as the matrix. A preferred control-release material for use as the matrix is hydroxypropylmethylcellulose which is hydrophillic in nature.

The material comprising the matrix can be added to the other constituents from which the mini-tablet is formed. The amount used will depend on various factors, including, for example, the desired release properties for the beraprost, the amount of beraprost to be delivered, the size of the mini-tablet, and the particular material(s) being used. It is believed that the amount of matrix used will typically fall within the range of about 10 to about 80 wt. % based on the total weight of the composition. Delayed-Release Component

The delayed-release of DR component of the formulation comprises beraprost in a formulation such that there is a lag time of about 6 hours (measuring from the time of ingestion) before any significant amount of beraprost is released in the body and thereafter the beraprost of the IR component is released over a period of time of at least about 18 hours.

The delayed-release or DR component of the formulation comprises two or more sub-components which contain beraprost and which function to (1) control the release of the beraprost in the body in a period of time of about 6 to about 12 hours after ingestion of the formulation; and (2) control the release of the beraprost in the body in a period of time of about 12 to about 18 hours after ingestion of the formulation. The DR component includes means to extend the release time of the beraprost, as indicated above. Such means can include, for example, one or more coatings which functions to delay and extend the release time of the beraprost in each of subcomponents of the DR component. In preferred form, the DR component comprises two sub-components, namely, DRl which has the release characteristics of (1) above and DR2 which has the release characteristics of (2) above.

In particularly preferred form, each of the DRl and DR2 components is in the form of mini-tablets and is prepared by coating an SR mini-tablet which contains the beraprost associated with a matrix which comprises a material that delays and gradually extends the time of release of the beraprost from the mini-tablet. The coatings which are applied to the components are formed from a rate controlling polymer that is applied in an amount that provides the desired release characteristics. Particularly preferred rate-control polymers for use in the coating composition are methacrylate-based coating materials, for example, those sold under the registered trademark Eudragit. A particularly preferred coating composition comprises a mixture of two rate-control polymers, one of the polymers being an anionic polymer of methacrylic acid and methacrylates having a COOH group. Suctr anionic polymers are available in the form of an aqueous dispersion with the anionic polymer having water solubility characteristics that are dependent on the pH of the aqueous medium in contact with the polymer. Species of the anionic polymer have solubility characteristics such that they dissolve in an aqueous medium having a pH of above 5.5. When present in a coating, the polymer dissolves as the coated component comes in contact with body fluids having a pH in excess of 5.5. As the polymer dissolves, channels appear in the coating for the release of the beraprost.

The other polymer for use in the coating is a copolymer of acrylate and methacrylates having a quaternary ammonium group. The water solubility characteristics of this type polymer are not dependent on pH of the aqueous medium in that the polymer is insoluble in aqueous medium irrespective of the pH thereof. A coating formed from this type polymer has low permeability and, accordingly, the rate of release of the beraprost is relatively low.

As will be observed from a reading of Example No. 1 below, the release of the beraprost from the DRl and DR2 components can be controlled by the amount of coating applied to the mini-tablets. The amount of polymer comprising the coated mini-tablet can vary over a wide range, for example, about 5 to 40 wt. %. The coating composition can be applied by any suitable method, including, for example, spray application using a fluidized bed coater or a pan coating system. The coating composition can be dried and/or cured at room or elevated temperature under conditions which are suitable for drying/curing the polymer comprising the coating.

The amount of beraprost contained within the formulation is an amount which is effective to treat the condition of the user on a daily basis. Although the effective amount will tend to vary depending on the particular condition being treated, the identity of the user, and other factors, it is believed that, for the treatment of peripheral vascular disease, thrombosis, pulmonary ischemia, pulmonary hypertension, diabetes, and neuropathy, the daily dosage of the beraprost will be prescribed at about 120 to about 180 meg. The amount of beraprost to include in each of the various components comprising the formulation is an amount which gives the desired release profile for the particular component and thus, the overall desired release profile. A recommended amount of the beraprost for each of the components comprising the formulation is based on the IR component's containing about 5 wt. % of the total amount of beraprost in the daily formulation and each of the SR, DRl and DR2 components containing an equal amount of the remaining 95 wt. % of the beraprost in the formulation. In preferred form, the formulation for use once a day is contained within a single capsule, for example, a hard gelatin capsule of 00 to 5, preferably size 3.

As exemplary of a desired beraprost release profile for a daily dosage of 180 meg of beraprost involving use of the formulation of the present invention, reference is made to the graph below which shows an ideal plasma concentration of beraprost over a period of time of about 20 hours. During the 20-hour period, the beraprost is released in the body initially in the stomach and then in the small and large intestines.

Beraprost PK Simulation

Examples

Example No. 1

The first example is illustrative of the preparation of a formulation of the present invention and includes a description of the formulation's components in the form of mini-tablets which are placed in a capsule for use. The formulation is comprised of three types of mini-tablets, namely: instant-release (IR) mini-tablets, sustained-release (SR) mini-tablets, and (DR) delayed-release mini-tablets.

Instant-Release Mini-tablets

The following materials were used to make the IR mini-tablets.

Materials Quantity, g beraprost sodium (beraprost) 0.5 lactose monohydrate 869.5 hydroxypropylmethylcellulose (HPMC) 20 starch 1500 100 magnesium stearate 10 purified water 380

The mini-tablets were formed from granules which were prepared from an aqueous solution containing a binder and beraprost by a wet granulating method that involved the use of a top-spray fluid-bed system. The aqueous solution was prepared by dissolving the HPMC in the water and adding thereto the beraprost which dissolved therein. The fluid-bed system was charged with the lactose monohydrate and the aqueous solution was sprayed onto the lactose monohydrate at an outlet temperature of about 22 °C and at a spray rate of about 10 to 15 g/minute. After all of the solution was applied, the resulting granules were dried for 20 minutes in the fluid bed system. The granules were blended with the starch (disintegrant) for 15 minutes, after which the magnesium stearate (lubricant) was added and the mixture was blended for an additional three minutes to provide granules which were formed into tablets using a rotary tablet press (Piccolo) equipped with 3 mm tablet tooling to a target hardness of 20N by the following steps. The theoretical quantity of beraprost sodium per IR mini- tablet is 10 meg.

Sustained-Release Mini-tablets

The following materials were used to make the SR mini-tablets.

Materials Quantity, g beraprost sodium 2.8 lactose monohydrate 375.2

HPMC, Methocel E6LV 10

HPMC, sieved Methocel K100M (<250 micron) 600 fumed silica, Aerosil 200 2 magnesium stearate 10 purified water 200

As with the aforementioned IR mini-tablets, the SR mini-tablets were formed from granules which were prepared from an aqueous solution containing a binder and beraprost by a wet granulating method that involved the use of a top-spray fluid-bed system. The aqueous solution was prepared by dissolving the HPMC in the water and adding thereto the beraprost which dissolved therein. The fluid-bed system was charged with the lactose monohydrate and the aqueous solution was sprayed onto the lactose monohydrate at an outlet temperature of about 22 °C and at a spray rate of about 15 g/minute. After all of the solution was applied, the resulting granules were dried for 10 minutes in the fluid bed system. The fumed silica (flow-control agent) and the HPMC were blended for one minute to form a uniform mixture of these components. The aforementioned granules were added to the mixture and blended for 10 minutes, after which the magnesium stearate was added and the resulting mixture was blended for an additional three minutes to form a composition which was formed into tablets using a rotary tablet press (Piccolo) equipped with 3 mm tablet tooling to a target hardness of 20N. The theoretical quantity of beraprost sodium per mini-tablet is 56.67mcg.

Delayed-Release Mini-tablets

Two sub-components, both in the form of mini-tablets and referred to as "DRl" and "DR2", were prepared. The DRl mini-tablets are effective in controlling the release of beraprost over a period of time of about six to 12 hours and the DR2 mini- tablets are effective in controlling the release of beraprost over a period of time of about 12 to 18 hours. Each of the DRl and DR2 mini-tablets was prepared in the same manner as the aforementioned SR mini-tablets of the present example and they were then coated with a coating composition comprising the following materials.

Materials Quantity, g

aqueous dispersion of acrylate/methacrylate copolymer with quaternary ammonium group 760 aqueous dispersion of anionic polymer of methacrylic acid and methacrylates with a COOH group 40 dibutylsebecate (DBS) 48 talc 72 simethicone emulsion 2 purified water 1082 The source of the copolymer referred to above is Eudragit^® RS 30D which is an aqueous dispersion containing the copolymer; the copolymer is referred to as being "pH-independent", that is, it is insoluble in aqueous media irrespective of pH and, therefore, exhibits a low permeability. It is recommended for forming coatings for sustained-release pharmaceutical formulations. The source of the anionic polymer referred to above is Eudragit^® L 30 D-55 which is an aqueous dispersion of the polymer. A coating formed from the polymer has a solubility in water which is pH- dependent, the coating being soluble at a pH above 5.5. The polymer is recommended for use in forming enteric coatings for controlled release of drugs in the duodenum.

The aqueous dispersions were mixed together for five minutes and thereafter the DBS was added gradually thereto and mixed therewith for five minutes. The simethicone emulsion was added to the resulting mixture and mixed therein for five minutes. The resulting mixture was combined with a mixture of the talc and the water. After mixing for five minutes, there was formed an aqueous coating composition which included the aforementioned polymeric film-forming constituents.

The coating composition was sprayed onto the DR mini-tablets using the Wurster Process at an outlet temperature of about 30 °C and at a spray rate of about 10 g/minute. Those DR mini-tablets that were sprayed with an amount of coating composition such that the resulting coating comprised 5 wt. % of the total weight of the tablet were the DRl mini-tablets, whereas, those sprayed with a greater amount of composition such that the coating comprised 10 wt. % of the tablet were the DR2 mini-tablets. Each of the coated DR mini-tablets contained a theoretical quantity of beraprost sodium of 56.67 meg. Capsule Containing Mini-Tablet Formulation of Example No. 1 and Evaluation

A gelatin capsule filled with one each of the IR mini-tablet, the SR mini-tablet, the DRl mini-tablet, and the DR2 mini-tablet, contains 180 meg. Oral ingestion of one such capsule daily will deliver to the patient a therapeutically effective amount of beraprost sodium.

Speaking generally, the release profile of each of the mini-tablets of Example No. 1 was evaluated by placing mini-tablets in aqueous-based solution(s) which mimic relevant body environments.

In vitro dissolution of IR mini-tablets was measured by placing the tablets in 0.01 N HCl. The dissolution was as follows.

Time, min % Released 5 94.8

10 95.1

15 100.0

The in vitro dissolution of SR mini-tablets was measured by placing the mini- tablets initially in 0.01 N HCl for 2 hours and thereafter in a phosphate buffer solution having a pH of 6.8. The dissolution was as follows.

Time, hrs % Released

1 27.3

2 46.6 4 74.8 6 88.0

In vitro dissolution of DR mini-tablets was measured in the same manner as that used to measure the in vitro dissolution of the SR mini-tablets. The dissolution was as follows. 5 wt. % DRl coating 10 wt. % DR2 coatine

Time, hrs % Released % Released

1 3.1 1.1

2 6.9 1.2

3 10.6 1.4

4 21.4 1.6

6 41.8 2.3

8 58.0 4.6

10 69.8 8.8

12 78.5 15.1

14 83.8 22.2

16 84.9 27.8

18 85.9 31.8

22 84.1 35.7

Example No. 2

The second example is illustrative of the preparation of a formulation of the present invention and includes a description of the formulation's components in the form of beads. The formulation is comprised of three types of beads, namely: instant- release (IR) beads, sustained-release (SR) beads, and (DR) delayed-release beads.

Instant-Release Beads

The following materials were used to make the IR beads.

Materials Quantity, g

beraprost sodium (beraprost) 0.7556 hydroxypropylmethylcellulose (HPC), Methocel E6LV 30 purified water 750 non-pareil seeds 970 IR beads were produced from a beraprost solution in a wet granulating method involving the use of a bottom-spray fluid-bed system. In forming the beraprost solution, the HPMC (binder) was added to the water and mixed for about 30 minutes until dissolved and thereafter the beraprost was added to the solution and mixed until dissolved. A fluid-bed system was charged with the non-pareil seeds and the beraprost solution was sprayed onto the seeds using the Wurster Bottom Spray Method at an outlet temperature of between 30-36°C, at a spray rate of between about 9 to 18 g/min, and at an atomizing air pressure of between 1.6 to 1.8 bar. After all of the solution was applied, the IR beads were dried for ten minutes in the fluid bed system at an inlet temperature of 35 °C. One g of IR beads contains about 755 meg of beraprost.

Sustained-Release Beads

SR beads were produced by coating in a bottom-spray fluid-bed system IR beads made as per the IR bead example above with a coating composition that is similar to the coating composition used to coat the DRl and DR2 minitablets of Example No. 1. The coating composition comprised the following materials.

Materials Quantity, g

aqueous dispersion of acrylate/methacrylate copolymer with quaternary ammonium group 1268 aqueous dispersion of anionic polymer of methacrylic acid and methacrylates with a COOH group 66.7 dibutylsebecate (DBS) 80 talc 120 simethicone emulsion 5 purified water 3462 The talc was added gradually to the water with stirring and the resulting dispersion was stirred for 30 minutes. The simethicone emulsion was added gradually to the dispersion and the resulting mixture was stirred for five minutes. The DBS was added gradually to the aqueous dispersion containing the copolymer and mixed for five minutes, after which the aqueous dispersion of the anionic polymer was added gradually thereto and mixed until dispersed. The talc-containing mixture was added gradually to the polymer-containing mixture and the resulting composition was mixed for 30 minutes to form the coating composition that was used tocoat the SR beads.

The coating of the SR beads involved charging 900 g of the IR beads described above in this example to the bottom-spray, fluid-bed system and spraying the IR beads with the aforementioned coating composition using the Wurster Bottom Spray Method at an outlet temperature of between 26 to 29 °C, at a spray rate of between about 10 to 20 g/min, and at an atomizing air pressure of 1.8 bar. After the application of the coating composition, the beads were dried for five minutes in the fluid bed system at an inlet temperature of 36 °C and then cured for 20 hours in an oven at 40 °C.

Delayed-Release Beads

The DRl beads were produced by applying to the coated SR beads described above a coating composition described below and the DR2 beads were produced by applying to the aforesaid coated SR beads an intermediate coating and a top-coating utilizing the coating composition described below. The coatings were applied to the DRl and DR2 beads utilizing a bottom-spray fluid-bed system.

The coating composition used to make the coated DRl beads comprised the following materials. Materials Quantity, g aqueous dispersion of anionic polymer of methacrylic acid and methacrylates with a COOH group, Eudragit FS 30D (polymer soluble above pH 7.0) 666.7 talc 60 triethyl citrate (TEC) 10 purified water 263.3

The talc was added gradually to the water with stirring and the talc-water dispersion was stirred for 30 minutes. The TEC was added gradually to the dispersion and the resulting dispersion was mixed for two minutes. The TEC-water-talc dispersion was added to the Eudragit FS 30D and the resulting composition was mixed to form the coating composition.

The coating of the DRl beads involved charging 800 g of the aforesaid coated SR beads to the bottom-spray, fluid-bed system and spraying the coated SR beads with the coating composition described immediately above using the Wurster Bottom Spray Method at an outlet temperature of between 26 to 28° C, at a spray rate of between about 8 to 10 g/minute, and at an atomizing air pressure of 1.6 bar. After the application of the coating composition, the beads were dried for ten minutes in the fluid bed system at an inlet temperature of 33 °C and cured for 20 hours in an oven at 40°C.

The coating composition used to form the intermediate coating on the DR2 beads comprised the following materials.

Materials wt. %

hydroxypropylmethylcellulose (HPMC) ,

Methocel E6LV 3.8 silicon dioxide 1

purified water 95.2 The HPMC was dissolved in the water and the silicon dioxide was added to the solution and mixed therein for 2 minutes. The HPC was added to the solution and mixed until dissolved forming the coating composition (hereafter "the IC coating composition").

The application of the intermediate coating involved charging 800 g of the aforementioned coated SR beads to the bottom-spray, fluid-bed system and spraying the coated SR beads with the IC coating composition using the Wurster Bottom Spray Method at an outlet temperature of between 26 to 28 °C, at a spray rate of between about 8 to 10 g/minute, and at an atomizing air pressure of 1.6 bar. After the application of the IC coating composition, the coated beads were dried for ten minutes in the fluid-bed system at an inlet temperature of 33 °C.

The top-coating of the "intermediate" coated DR2 beads was applied thereto by charging the beads to the bottom-spray, fluid-bed system and spraying the beads with a coating composition comprising the composition used to coat the DRl beads of this example using the Wurster Bottom Spray Method at an outlet temperature of between 26 to 28 °C, at a spray rate of between about 8 to 10 g/minute, and at an atomizing air pressure of 1.6 bar. After application of the top-coat coating composition, the beads were dried for ten minutes in the fluid-bed system at an inlet temperature of 33 °C and cured for about 20 hours in an oven at 40 °C.

The amount of beraprost in the SR and IR beads was in the range of about 590 to about 660 mcg/g of beads, depending on the type and amount of coating applied to the beads.

Claims

1. A formulation which is capable of being taken orally for the delivery of beraprost sodium and which comprises the following components, each of which includes the beraprost sodium: (A) an instant-release (IR) component which releases substantially all of the beraprost sodium thereof in the stomach within about 15 minutes after ingestion; (B) a sustained-release (SR) component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body over a period of time of about 6 hours after ingestion; and (C) a delayedrelease (DR) component which includes: (i) at least one sub-component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body in a period of time of about 6 to about 12 hours after ingestion; and (ii) at least one other sub-component which has associated therewith a material that is effective in controlling the release of beraprost sodium in the body in a period of time of about 12 to about 18 hours after ingestion.

2. A formulation according to Claim 1 wherein said IR component comprises a binding agent selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinyl pyrrodine.

3. A formulation according to Claim 1 wherein said SR component comprises a mini-tablet which has therein a coating that delays the release of the beraprost sodium from the mini-tablet.

4. A formulation according to Claim 3 wherein said coating comprises a control- release polymer selected from the group consisting of ammonio methacrylate copolymers and methacrylate acid polymers and a mixture thereof.

5. A formulation according to Claim 1 wherein said SR component comprises a mini-tablet which contains the beraprost sodium associated with a matrix that comprises a material which delays and gradually extends the time of release of the beraprost sodium from the mini-tablet.

6. A formulation according to Claim 5 wherein said matrix material comprises hydroxypropylmethylcellulose .

7. A formulation according to Claim 1 in which the DR component includes but one subcomponent (C)(i) and but one of said other components.

8. A formulation according to Claim 7 wherein each of the subcomponents is in the form of a mini-tablet comprising the beraprost sodium associated with a matrix and having thereon a coating comprising a rate-controlling polymer.

9. A formulation according to Claim 8 in which the rate-controlling polymer is methacrylate based.

10. A formulation according to Claim 8 in which the rate-controlling polymer comprises a mixture of: (A) an anionic polymer of methacrylic acid and methacrylates having a COOH group; and (B) a copolymer of acrylate and methacrylates having a quaternary ammonium group.

11. A formulation according to Claim 1 in the form of a dose which contains about 120 to about 180 meg of beraprost sodium.

12. A method for supplying therapeutic amounts of beraprost sodium to serum of an animal through the animal's gastrointestinal tract by oral ingestion of a therapeutically effective amount of a formulation as defined in any of the preceding formulation claims.

13. A method according to Claim 12 in which the animal is a human.

14. A method according to Claim 13 in which the formulation is ingested by said human to treat a condition selected from the group consisting of peripheral vascular disease, thrombosis, pulmonary ischemia, pulmonary hypertension, diabetes, and neuropathy.

15. A method according to Claim 13 wherein the formulation is ingested by said human to treat chronic arterial inclusion.

16. A method according to Claim 13 in which a single dose of the formulation is ingested daily.

17. A method according to Claim 13 in which the single dose comprises the dose of Claim 11.