WO1996025922A2

WO1996025922A2 - Banded prolonged release active agent dosage form

Info

Publication number: WO1996025922A2
Application number: PCT/US1996/001848
Authority: WO
Inventors: Patrick S.-L. Wong; David Edmil Edgren; Liang C. Dong; Vincent J. Ferrari
Original assignee: Alza Corp
Current assignee: Alza Corp
Priority date: 1995-02-24
Filing date: 1996-02-09
Publication date: 1996-08-29
Anticipated expiration: 1997-08-24
Also published as: KR19980702469A; PT810856E; CN1175901A; NZ303809A; JPH11500728A; DE69612481T2; EP0810856B1; FI973452A0; GR3035743T3; US6020000A; US5667804A; DE69612481D1; FI973452L; US6316028B1; EP0810856A2; NO973840L; MX9706484A; NO973840D0; AU5022696A; CN1142771C

Abstract

The present invention is directed to an active agent dosage form which is useful for the prolonged delivery of an active agent formulation to a fluid environment of use. The active agent dosage form is a matrix that has on its surface two or more insoluble bands. The invention is also directed to the method for making the active agent dosage form.

Description

1 BANDEDPROLONGEDRELEASEACTIVEAGENTDOSAGEFORM

2

3 FIELD OF THE INVENTION

4 s The present invention is related to the prolonged delivery of an active

6 agent. More particularly, it is a banded active agent dosage form useful for

7 delivering a beneficial agent to a fluid environment of use. The invention is β also directed to the method of making the banded active agent dosage form.

9 o BACKGROUND OF THE INVENTION 1 2 Tablets, capsules, caplets and many other types of devices have been 3 used for dispensing a beneficial agent to a fluid environment of use. Easy manufacture of a device that provides for prolonged delivery of an active s agent in a controlled and predictable manner continues to be a goal, 6 especially in the area of drug delivery. 7 8 US Patent No. 4,290,426 to Luschen et al describes a cylindrical 9 dispenser for releasing a beneficial agent into a fluid environment at a rate 0 that is governed by the fluid induced relaxation of a polymeric agent 1 contained within the dispenser. The cylindrical dispenser includes an 2 impermeable container that has within it a reservoir and a passageway from 3 the reservoir to the exterior of the container. The reservoir contains a 4 polymer and a beneficial agent. The polymer imbibes fluid from the 5 environment and thereby undergoes relaxation, releasing the beneficial agent 6 from the device. The amount of agent released is dependent on the rate of 7 relaxation of the polymer over time. 8 9 Coated dosage forms have also been suggested for delivery of a 0 controlled amount of a beneficial agent over a prolonged period of time. US 1 Patent No. 5,256,440 describes a process for producing a film coated dosage ι form. A continuous groove is inscribed in a dosage form core. A latex film is

2 coated onto the core, the groove defining a fixed zone and a detachable zone

3 for the film. The detachable portion of the latex film detaches when it is

4 exposed to the environment of use, thereby exposing a discrete portion of the

5 dosage form core surface. The remainder of the film remains attached to the

6 dosage form core. The exposed portion of the dosage form surface erodes

7 and releases active agent to the environment of use.

8

9 Coated tablets for constant and prolonged drug release are described ιo by Conte et al in J. Controlled Release. Vol. 26, (1993) pages 39-47. These ιι GEOMATRIX™ Systems are swellable matrices that are coated or tableted

12 with polymeric barrier layers. Release performances of the systems are i3 modulated as a result of the restriction of the releasing surface by the

1 polymeric barrier layer coatings. As the extent of coating of the system's is surface is increased, the release kinetics of the system shift toward constant

16 release. These systems are further described in US Patent No. 4,839,177 to

17 Colombo et al.

18

19 As can be observed in the above-referenced patents and publications,

20 devices have been described that provide for prolonged delivery of an active

21 agent. However, there remains a continuing need for improved systems for

22 delivering an active agent in a reliable and reproducible manner that are easy

23 and inexpensive to manufacture.

24

25 SUMMARY OF THE INVENTION

26

27 We have observed that devices such as those described above will

28 provide for prolonged delivery of an active agent formulation to a fluid

29 environment of use but that these devices may not necessarily provide for

30 controlled and reliable release. Accordingly, the present invention is directed

31 to a dispensing device that will release an active agent formulation in a ι reliably controllable manner, and further that is easy and inexpensive to

2 manufacture.

3

4 The invention is directed to an active agent dosage form for the

5 prolonged delivery of an active agent to a fluid environment of use. The ε surface of an active agent formulation matrix contains two or more insoluble

7 bands.

8

9 In one aspect, the invention is directed to an active agent dosage form ιo for the prolonged delivery of an active agent to a fluid environment of use. ιι Two or more insoluble bands surround an active agent formulation matrix.

12 The bands drop off the matrix as it erodes, providing a decreasing path

13 length for delivery of the drug.

14 is In another aspect, the invention is to an active agent dosage form for

16 the prolonged delivery of an active agent to a fluid environment of use where

17 two or more insoluble bands are printed or otherwise securely affixed to the is surface of the dosage form. The surface area of the matrix between the

19 bands erodes delivering active agent to the fluid environment of use. The

20 surface area not covered by the rings increases with time.

21

22 The invention is also directed to a method for preparing the active

23 agent dosage form for prolonged delivery of an active agent. An active agent

24 formulation matrix is prepared and insoluble material is placed or printed onto

25 the formulation to form two or more insoluble bands on the surface of the

26 matrix.

27 DESCRIPTION OF THE DRAWINGS

The figures are not drawn to scale, but are set forth to illustrate various embodiments of the invention. Like numbers refer to like structures.

FIG. 1 is a side elevational view of one embodiment of the delivery device of the present invention, the device being in prepared form prior to placement in the environment of use.

FIG. 2 shows the device of FIG. 1 in operation after placement in the environment of use, showing erosion of the active agent formulation matrix.

FIG. 3 shows the device of FIG. 1 in operation after sufficient erosion of the matrix has caused separation of the banded sections of the device.

FIG. 4 is a side elevational view of a second embodiment of the delivery device of the present invention, the device being in prepared form prior to placement in the environment of use.

FIG. 5 shows the device of FIG. 4 in operation after sufficient erosion of the matrix has caused separation of the sections of the device.

FIG. 6 is a side elevational view of a third embodiment of the delivery device of the present invention, the device being in prepared form prior to placement in the environment of use.

FIGs. 7, 8, 9, 10 and 11 (A and B) are graphs showing the performance of ibuprofen matrices with bands of varying number and placed in different positions on the matrices. FIGs. 7A, 8A, 9A, 10A and 11 A show the release rates of the drugs from the devices while 7B, 8B, 9B, 10B and 11 B show the cumulative doses of the drugs over a delivery period of up to 20 hours. 1

2 FIGs. 12, 13, 14 and 15 are graphs showing the release rates of ibuprofen

3 matrices with bands of varying number for a period of up to 4 hours.

4

5

6 DETAILED DESCRIPTION OF THE INVENTION

7 β The present invention provides a device that is useful for the prolonged

9 delivery of an active agent formulation to a fluid environment of use.

10 ιι Definitions

12

13 The phrase "prolonged delivery" intends a period of delivery that lasts for

14 several hours to about 24 hours, usually up to about 20 hours, and often is between about 3 and 16 hours.

16

17 By "insoluble" is intended a material that will not dissolve, degrade or is erode in the environment of use during the delivery period.

19

20 By "apply" or "applied" or "application" intends the substantially uniform

21 deposition of insoluble material, in liquid or in molten form, onto the active 2 agent formulation matrix. A variety of techniques may be used to apply the 3 insoluble material, including but not limited to Gravure-type printing, extrusion coating, screen coating, spraying, painting, and the Capsealer process

25 developed by TAIT Design & Machine Co., Manheim, PA. 6 7 The term "active agent formulation" intends the active agent or drug β optionally in combination with pharmaceutically acceptable carriers and 9 additional inert ingredients. 0 ι The term "active agent formulation matrix", as used herein, comprises the

2 active agent formulation in combination with a hydrophilic polymeric material.

3

4

5 The term "active agent dosage form" intends the active agent formulation

6 matrix as defined above with two or more bands of an insoluble material

7 applied onto its surface.

8

9 As used herein, the terms "therapeutically effective" amount or rate refer ιo to the amount or rate of the active agent needed to effect the desired ιι pharmacologic, often beneficial, result.

12

13 The dispensing devices of the invention find use, for example, in humans

1 or other animals. The environment of use is a fluid environment and can is comprise the stomach, the intestinal tract, or a body cavity such as the

16 peritoneum or vagina. A single dispensing device or several dispensing

17 devices can be administered to a subject during a therapeutic program.

18

19 FIG. 1 depicts, in side elevational view, one embodiment of the delivery

20 device according to the present invention. The device is shown in prepared

21 form prior to placement in the environment of use. Dispensing device 1 is

22 shown in FIG. 1 to comprise a cylindrically shaped active agent formulation

23 matrix 12. The ends 14 and 16 of the matrix are preferably rounded and

2 convex in shape in order to ensure ease of insertion into the environment of

25 use. Bands 20, 22 and 24 concentrically surround the cylindrical matrix 12.

26

27 FIG. 2 shows dispensing device 1 in operation after having been placed in

28 the fluid environment of use. The active agent formulation matrix 12 between

29 bands 20, 22 and 24 has begun to erode, thereby releasing active agent to

30 the fluid environment of use.

31 1 ι FIG. 3 shows dispensing device 1 in operation after a length of time in the

2 fluid environment of use. The active agent formulation matrix 12 has eroded

3 between bands 20, 22 and 24 to such an extent that the matrix 12 is now in three pieces, 30, 32 and 34. Erosion will continue until the matrix portions of

5 each of the pieces have completely eroded. Bands 20, 22 and 24 will

6 thereafter be expelled from the fluid environment of use.

7 β FIG. 4 shows, in side elevational view, a second embodiment of the

9 delivery device according to the present invention. The device is shown in ιo prepared form prior to placement in the environment of use. Dispensing ιι device 50 comprises a cylindrically shaped active agent formulation matrix 52

12 with convex ends 54 and 56. Bands 60, 62, 64 and 66 concentrically

13 surround the cylindrical matrix 52.

14 is FIG. 5 shows dispensing device 50 in operation after a length of time in

16 the fluid environment of use. The active agent formulation matrix 52 has

17 eroded from the exposed ends of bands 60, and 66 to such an extent that the is device 50 is now in three pieces, 70, 72, and 74. The arrows show the

19 erosion of the matrix and therefore the extent of active agent delivery. 0 Erosion will continue from the exposed ends of bands 62 and 64 until the 1 matrix has completely eroded. Bands 60, 62, 64 and 66 will thereafter be 2 expelled from the fluid environment of use. 3

24 The active agent itself may be in liquid, solid or semisolid form. The 5 active agent formulation may contain additional materials and may be 6 designed in a multitude of ways to provide a specific drug delivery profile. 7 One embodiment comprises a formulation that contains a biologically 8 acceptable hydrophilic polymer which is capable of slow dispersion in the 9 environmental fluid. In another embodiment, the formulation may contain a 0 hydrophilic polymer and a surfactant so that the formulation is susceptible to 1 erosion in the environment. In still another embodiment, the formulation may %

ι include a solid surfactant and provide drug delivery in a finely dispersed form.

2 In yet a further embodiment, the formulation may include coated

3 microspheres of an active agent and an adjuvant. The active agent and adjuvant can be delivered simultaneously from the microspheres either by

5 diffusion or by osmosis. Suitable materials useful as active agent carriers

6 and excipients are known in the art and are disclosed in US Patent Nos.

7 4,595,583 and 4,874,388, for example.

8

9 The terms "active agent" and "drug" are used interchangeably herein and ιo refer to an agent, drug, compound, composition of matter or mixture thereof ιι which provides some pharmacologic, often beneficial, effect. This includes

12 pesticides, herbicides, germicides, biocides, algicides, rodenticides,

13 fungicides, insecticides, antioxidants, plant growth promoters, plant growth

1 inhibitors, preservatives, antipreservatives, disinfectants, sterilization agents, is catalysts, chemical reactants, fermentation agents, foods, food supplements,

16 nutrients, cosmetics, drugs, vitamins, sex sterilants, fertility inhibitors, fertility

17 promoters, microorganism attenuators and other agents that benefit the is environment of use. As used herein, the terms further include any

19 physiologically or pharmacologically active substance that produces a

20 localized or systemic effect or effects in animals, including warm blooded

21 mammals, humans and primates; avians; domestic household or farm animals

22 such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals

23 such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and

24 the like. The active drug that can be delivered includes inorganic and

25 organic compounds, including, without limitation, drugs which act on the

26 peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal

27 muscles, the cardiovascular system, smooth muscles, the blood circulatory

2β system, synoptic sites, neuroeffector junctional sites, endocrine and hormone

29 systems, the immunological system, the reproductive system, the skeletal

30 system, autacoid systems, the alimentary and excretory systems, the

31 histamine system and the central nervous system. Suitable agents may be ι selected from, for example, proteins, enzymes, hormones, polynucleotides,

2 nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides,

3 steroids, hypnotics and sedatives, psychic energizers, tranquilizers,

4 anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, anti-

5 inflammatories, local anesthetics, muscle contractants, antimicrobials,

6 antimalarials, hormonal agents including contraceptives, sympathomimetics,

7 polypeptides and proteins capable of eliciting physiological effects, diuretics,

8 lipid regulating agents, antiandrogenic agents, antiparasitics, neoplasties,

9 antineoplastics, hypoglycemics, nutritional agents and supplements, growth ιo supplements, fats, ophthalmics, antienteritis agents, electrolytes and ιι diagnostic agents.

12

13 Examples of beneficial agents useful in this invention include

14 prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, is mecamylamine hydrochloride, procainamide hydrochloride, amphetamine

16 sulfate, methamphetamine hydrochloride, benzphetamine hydrochloride,

17 isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol chloride, is methacholine chloride, pilocarpine hydrochloride, atropine sulfate,

19 scopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin

20 hydrochloride, methylphenidate hydrochloride, theophylline cholinate,

21 cephalexin hydrochloride, diphenidol, meclizine hydrochloride,

22 prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate,

23 anisindione, diphenadione erythrityl tetranitrate, digoxin, isoflurophate,

24 acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide,

25 tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum

26 aspirin, methotrexate, acetyl sulfisoxazole, hydrocortisone,

27 hydrocorticosterone acetate, cortisone acetate, dexamethasone and its

28 derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-

29 β-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 0 17-β-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, 1 norethindrone, norethisterone, norethiederone, progesterone, norgesterone, \o

ι norethynodrel, aspirin, acetaminophen, indomethacin, naproxen, fenoprofen,

2 sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol,

3 atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, calcium gluconate,

5 ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac,

6 ferrous lactate, vincamine, phenoxybenzamine, diltiazem, milrinone,

7 captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, β fenbufen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal, 9 nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, ιo tiapamil, gallopamil, amlodipine, mioflazine, lisinopril, enalapril, captopril, ιι ramipril, enalaprilat, famotidine, nizatidine, sucralfate, etintidine, tetratolol,

12 minoxidil, chlordiazepoxide, diazepam, amitriptyline, and imipramine. Further

13 examples are proteins and peptides which include, but are not limited to,

14 insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and is pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic

16 hormone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin

17 releasing hormone, bovine somatotropin, porcine somatropin, oxytocin, is vasopressin, prolactin, somatostatin, lypressin, pancreozymin, luteinizing

19 hormone, LHRH, interferons, interleukins, growth hormones such as human

20 growth hormone, bovine growth hormone and porcine growth hormone,

21 fertility inhibitors such as the prostaglandins, fertility promoters, growth

22 factors, and human pancreas hormone releasing factor.

23

2 It is to be understood that more than one active agent may be

25 incorporated into the active agent formulation in a device of this invention,

26 and that the use of the term "agent" or "drug" in no way excludes the use of

27 two or more such agents or drugs.

28

29 The agents can be in various forms, such as uncharged molecules,

30 components of molecular complexes or nonirritating, pharmacologically

31 acceptable salts. Also, simple derivatives of the agents (such as ethers, ι esters, amides, etc) which are easily hydrolyzed by body pH, enzymes, etc,

2 can be employed.

3 The amount of active agent employed in the delivery device will be that

5 amount necessary to deliver a therapeutical ly effective amount of the agent to

6 achieve the desired result at the site of delivery. In practice, this will vary

7 widely depending upon the particular agent, the site of delivery, the severity β of the condition, and the desired therapeutic effect. Thus, it is not practical to

9 define a particular range for the therapeutically effective amount of active ιo agent incorporated into the device.

11

12 The hydrophilic polymeric material useful herein may comprise, i3 polysaccharides, methyl cellulose, sodium or calcium carboxymethyl i4 cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, is hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose and other

16 cellulose ethers, and polyethylene oxides (eg, Polyox®, Union Carbide).

17 Other materials useful as the hydrophilic polymeric material include but are is not limited to methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose

19 acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch,

20 maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl

21 acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid,

22 copolymers of ethacrylic acid or methacrylic acid (Eudragit™) or other acrylic

23 acid derivatives, sorbitan esters, natural gums, lecithins, pectin, alginates,

24 ammonia alginate, sodium or potassium alginate, calcium alginate, propylene

25 glycol alginate, potassium alginate, agar, gum arabic, gum karaya, locust

26 bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan

27 gum, scleroglucan, and blends of the above.

28

29 The pharmaceutically acceptable carrier useful herein may comprise more

30 than one ingredient, such as, for example, a buffer, a viscosity regulating II ι vehicle, a surfactant, a dye, a permeation enhancer, a proteinase inhibitor, or

2 other formulation ingredients and additives, as are known in the art.

3 In addition to design of the active agent formulation to provide a specific

5 drug delivery profile, the number, size, and placement of the insoluble bands

6 that are applied onto the active agent formulation matrix may be varied to

7 provide the desired drug delivery profile. For example, bands of from about β 0.1 mm to about 12 mm in width, preferably between about 0.5 and 8 mm,

9 may be applied onto the active agent formulation matrix surface. Further, ιo between about 2 and 10 bands may be used, but generally between about 2 ιι and 6 are affixed to the matrix. The bands may be placed close together (ie,

12 within about 0.5 mm of each other) or may be placed at opposite ends of the

13 matrix (ie, spaced about 8 to 12 mm apart). The insoluble material may be

1 any material that is nontoxic, biologically inert, nonallergenic and nonirritating is to body tissue, and that maintains its physical and chemical integrity; that is,

16 the bands do not erode or degrade in the environment of use during the

17 dispensing period. Insoluble materials from which the bands may be prepared ie include, for example, polyethylene, polystyrene, ethylene-vinyl acetate

19 copolymers, polycaprolactone and Hytrel® polyester elastomers (Du Pont).

20 Additional banding materials include but are not limited to polysaccharides,

21 cellulosics, powdered cellulose, microcrystalline cellulose, cellulose acetate,

22 cellulose actetate pseudolatex (such as described in U.S. Patent 5,024,842),

23 cellulose acetate propionate, cellulose acetate butyrate, ethyl cellulose, ethyl

24 cellulose pseudolatex (such as Surelease® as supplied by Colorcon, West

25 Point, PA or Aquacoat™ as supplied by FMC Corporation, Philadelphia, PA),

26 nitrocellulose, polylactic acid, poly- glycolic acid, polylactide glycolide

27 copolymers, collagen, polycaprolactone, polyvinyl alcohol, polyvinyl acetate,

28 polyethylene vinylacetate, polyethylene teraphthalate, polybutadiene styrene,

29 polyisobutylene, polyisobutylene isoprene copolymer, polyvinyl chloride,

30 polyvinylidene chloride-vinyl chloride copolymer, copolymers of acrylic acid

31 and methacrylic acid esters, copolymers of methylmethacrylate and ι ethylacrylate, latex of acrylate esters (such as Eudragit® supplied by

2 RόhmPharma, Weiterstadt, Germany), polypropylene, copolymers of

3 propylene oxide and ethylene oxide, propylene oxide ethylene oxide block copolymers, ethylenevinyl alcohol copolymer, poly sulfone, ethylene

5 vinylalcohol copolymer, polyxylylenes, polyamides, natural and synthetic

6 waxes, paraffin, carnauba wax, petroleum wax, white or yellow bees wax,

7 castor wax, candelilla wax, rice bran wax, microcrystalline wax, stearyl β alcohol, cetyl alcohol, bleached shellac, este fied shellac, chitin, chitosan,

9 silicas, polyalkoxysilanes, polydimethyl siloxane, polyethylene glycol-silicone ιo elastomers, crosslinked gelatin, zein, electromagnetic irradiation crosslinked ιι acrylics, silicones, or polyesters, thermally crosslinked acrylics, silicones, or

12 polyesters, butadiene-styrene rubber, glycerol ester of partially dimerized

13 rosin, glycerol ester of partially hydrogenated wood rosin, glycerol ester of tall

14 oil rosin, glycerol ester of wood rosin, pentaerythritol ester of partially is hydrogenated wood rosin, pentaerythritol ester of wood rosin, natural or

16 synthetic terpene resin and blends of the above.

17 is The banding materials often are also formulated with plasticizers, and

19 optionally with wetting agents, surfactants, opacifiers, colorants, flavorants,

20 taste-masking agents, and the like. Examples of typical plasticizers are as

21 follows: polyhydric alcohols, polyethylene glycol, glycerol, propylene glycol,

22 acetate esters, glycerol triacetate, triethyl citrate, acetyl triethyl citrate,

23 glycerides, acetylated monoglycerides, oils, mineral oil, castor oil and the 4 like. 5 6 The rate of release of the active agent from the active agent dosage form 7 is predominantly controlled by erosion of the aqueous gel formed by 8 contacting the matrix with the fluid environment of use. The drug released, m ι at time t, is proportional to the surface area of the system and can be written 2 as

3 dm/dt = KA. (Equation 1 )

5

6 K is the erosion constant in mg/cm²hr and varies according to the m

7 A is the erosion area, β

9 The release profile dm/dt is constant if K and A remain constant.

10 ιι Substituting Equation 1 with the area of a cylindrical matrix with negligible

12 end effects gives

13

14 dm/dt = K2πRL (Equation 2)

15

16 L is the length of the cylinder and

17 R is the radius of the cylinder at time t.

18

19 The mass release at time t is

20

21 m = π [R₀ ²-R²]LCo (Equation 3)

22

23 Ro is the initial radius of the cylinder and

24 Co is the initial concentration of the drug in the cylinder.

25

26 Substituting Equation 3 into Equation 2 leads to

27

28 dR/dt = -K/Co (Equation 4)

29 b ι Integrating Equation 4 gives

2

3 R = Ro - (K/C₀)t (Equation 5)

4

5 The fraction amount of drug release, F, can now be defined by

6 substituting Equation 5 into Equation 3 as follows

7 β F = m/mo = π [R₀ ²-R²]LC₀ /( π R₀ ²LC₀) = 1 - [1 - Kt/(C₀R₀)]² (Equation 6)

9 ιo dF/dt = 2 K CoRo - (2 K²/C₀ ²Ro²)t (Equation 7)

11

12 Equation 7 indicates that the plot of the rate of active agent released from

13 a cylindrical dosage form without bands versus time will be linear and will

14 decrease with time, as is shown in Figure 7A. As drug is released from an is unbanded capsule, the diameter of the cylinder as well as the area of erosion

16 decreases. In contrast, as the polymeric core of the banded cylinder of this

17 invention shrinks, new surface area is created and exposed to the ie environment of use (see Figure 2). As a result, the amount of active agent

19 released over time may remain constant or may increase with time depending

20 on the rate of the new surface area being generated. By arrangement of the

21 number, size and location of bands on the dosage form, the total new surface

22 area created by erosion can be predicted and the desired release profile can

23 be achieved.

24

25 The bands may be placed onto the surface of the matrix such that, as the

26 matrix erodes, the bands become loose and drop off the matrix. These bands

27 are easily excreted from the gastrointestinal tract. As the number of bands

28 remaining on the surface of the matrix decreases, more matrix surface area

29 will be exposed. The matrix will therefore erode in a fashion that approaches

30 zero order.

31 l(c ι The bands may also be printed onto the surface of the matrix. The matrix

2 will erode where not covered by the bands as described above with reference

3 to FIGs. 1-5.

4

5 In order to prepare a device of the present invention, the active agent

6 formulation is first prepared and formed into a matrix of the desired size and

7 shape. The matrix in its initial prepared form is about the size and β dimensions of a size "5" to size "OOO" hard gelatin capsule. The cross-

9 sectional shape of the matrix may be circular or may be oval, triangular, ιo square, hexagonal or other shapes that are easily handled, especially by ιι patients with limited dexterity. The rings or bands are then placed onto the

12 surface of active agent formulation matrix or printed onto the surface using

13 conventional banding or printing techniques.

14 is In addition to the devices described above, embodiments are

16 contemplated that include non-uniform matrices. These devices may include

17 matrices with two or more active agents or two or more pharmaceutically

18 acceptable carriers. An example of a device 80 with a non-uniform matrix is

19 shown in FIG. 6. A lower portion 82 of the matrix material is formed from the

20 hydrophilic polymeric materials described above that erode over time upon

21 exposure to a fluid environment of use. An upper portion 84 of the matrix

22 material disintegrates upon placement in the fluid environment of use. The

23 latter portion of the matrix will provide for an initial pulse of active agent as

24 the material swells and separates from the rest of the matrix. The remaining

25 portion of the device, with bands 86 and 88 as described above, will provide

26 for the prolonged delivery of the same or a different active agent. Materials

2 that swell and disintegrate upon placement in the fluid environment of use 2β include, but are not limited to hydroxypropyl cellulose having a

29 hydroxypropoxyl content of 7 to 16 weight percent, crosslinked polyvinyl

30 pyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, cellulose

31 fiber and the like . π

The following examples are illustrative of the present invention. They are not to be construed as limiting the scope of the invention. Variations and equivalents of these examples will be apparent to those skilled in the art in light of the present disclosure, the drawings and the claims herein.

EXAMPLE 1

A delivery device according to the present invention was prepared as follows. 58 grams of the analgesic drug, ibuprofen, 25 grams of hydroxypropyl methylcellulose having a number average molecular weight of 9,200 grams per mole, and 15 grams of hydroxypropyl methylcellulose having a molecular weight of 242,000 grams per mole, were passed through a screen having a mesh size of 40 wires per inch. The celluloses each had an average hydroxyl content of 8 weight percent and an average methoxyl content of 22 weight percent. The resulting sized powders were tumble mixed. Anhydrous ethyl alcohol was added slowly to the mixed powders with stirring until a dough consistency was produced. The damp mass was then extruded through a 20 mesh screen and air dried overnight. The resulting dried material was re-screened through a 20 mesh screen to form the final granules. 2 grams of the tabletting lubricant, magnesium stearate, which had been sized through an 80 mesh screen, was then tumbled into the granules.

690 mg of the resulting granulation was placed in a die cavity having an inside diameter of 9/32 inch and compressed with deep concave punch tooling using a pressure head of 2 tons. This formed a longitudinal capsule core having an overall length, including the rounded ends, of 0.691 inch. The cylindrical body of the capsule, from tablet land to tablet land, spanned a distance of 12 mm. Each core contained a unit dose of drug of 400 mg. Rings of polyethylene having an inside diameter of 9/32 inch, a wall thickness 1 of .013 inch, and a width of 2 mm were then fabricated. These rings, or

2 bands, were press fitted onto the capsule to complete the dosage form.

3

4 EXAMPLE 2

5

6 Drug release studies were performed by placing the dosage forms in a

7 slotted basket. The inside diameter of the basket was 14 mm and the length β was 50 mm. The basket was attached to a reciprocating motor. The basket

9 was then immersed in 50 ml of simulated intestinal fluid at 37°C, and shaken ιo vertically in the media with a amplitude of 3.8 cm and a frequency of 99-101 ιι cycles per minute. After 1 hour of shaking, the basket was transferred to a

12 fresh 50 ml volume of the test media. This procedure was continued, hour by

13 hour, for nine hours. The systems then were allowed to release continuously

14 for another 13 hours to complete a 24 hour test duration. The release is receptor solutions were then analyzed for drug content by ultraviolet

16 spectroscopy. The release rate as a function of time and cumulative release

17 as a function of time were computed.

18

19 Figure 7-10A show the release rates of the ibuprofen cylindrical matrix

20 formulation described in Example 1 and Figures 7-10B show the cumulative

21 amount of drug released, FIGs. 7A and B show the 0.281 inch by 0.691 inch

22 longitudinal capsule with no bands, FIGs. 8A and B show the capsule with

23 one 2 mm band positioned in the middle of the capsule, FIGs. 9A and B show

24 the capsule with two 2 mm bands one positioned at each end of the capsule

25 with an 8 mm distance between the bands, FIGs. 10A and B show the

26 capsule with three 2 mm bands, one positioned in the middle of the capsule

27 and one positioned at each end with a distance of 3 mm between the bands.

28 The delivery rate approaches zero order as greater numbers of bands are

29 included. Further, as more of the surface area is covered by the insoluble so material, the release rate is prolonged. The total delivery times to release

31 90% of the initial dose are as follows: for no bands, 6.6 hours; for one 2 mm il ι band, 10.7 hours; for two 2 mm bands, 17.6 hours; and for three 2 mm bands,

2 19.2 hours.

3 EXAMPLE 3

5

6 Figure 11 A shows the release rate as a function of time of the ibuprofen

7 cylindrical matrix formulation described in Example 1 except that the system β banded with two rings was tested with a different positioning of the rings.

9 Figure 11 B shows the corresponding cumulative release versus time. The ιo two rings were positioned such that they were equispaced along the 12 mm ιι cylindrical body, with 2.7 mm between the land and the ring, and 2.7 mm

12 between the rings. A comparison of these patterns with the patterns

13 illustrated in Figures 9A and 9B, demonstrates that different patterns can be

14 achieved with different ring configurations. The total delivery time to deliver is 90% of the dose is 10.2 hours rather than 17.6 hours.

16 17

zo

1 EXAMPLE 4

2

3 A fast-release drug granulation was prepared as follows; 87 grams of

4 ibuprofen, 10 grams of hydroxypropyl cellulose having a hydroxypropoxyl

5 content of 11 weight percent, and 1 gram of hydroxypropyl methyl cellulose

6 having a hydroxypropoxyl content of 8 weight percent and a methoxy content

7 of 22 weight percent and having a number average molecular weight of 9,200 β grams per mole, were screened through a 40 mesh sieve. The sized

9 powders were mixed and anhydrous ethanol was added with stirring until a ιo uniform, damp mass was produced. The mixture was extruded through a 20 ιι mesh sieve. The elongated granules produced were air dried. The dried

12 granules were re-screened through a 20 mesh sieve. 2 grams of stearic acid

13 which had been passed through an 80 mesh sieve were tumble mixed into

14 the granules for 3 minutes.

15

16 690 mg of the granulation of Example 1 were filled into a die cavity having

17 an inside diameter of 9/32 inch and lightly compressed with deep concave ie punch tooling. The upper punch was removed and 230 mg of the fast-release

19 granulation was placed on the lightly compressed core. The upper punch

20 was returned to the die cavity and a 2 ton compression force was applied,

21 thereby forming a two-layered tablet. Two rings were press fitted onto the

22 690 mg portion of the dosage form according to the procedures specified in

23 Example 3.

24

25 An abrasion resistant, protective coating was applied to the banded, two-

26 layered tablet as follows. A coating solution was prepared by dissolving 63

27 grams of hydroxypropyl methylcellulose having a hydroxypropoxyl content of 2β 10 weight percent and a methoxy content of 29 weight percent with a number

29 average molecular weight of 11 ,900 grams per mole, and 7 grams of

30 polyethylene glycol having a molecular weight of 3,350 grams per mole, in

31 930 grams of water. The ringed tablets were then placed in a pan coating Z\ ι machine. The coating solution was sprayed onto the ringed tablet in a

2 current of warmed air until 40 mg of film were deposited on each tablet.

3

4 The resulting two-layer, film coated systems were tested for release of

5 drug according to the procedures describe in Example 2, except that the

6 release test media was simulated gastric fluid having a pH of approximately

7 1.2. In this test, the fast-release layer dispensed 200 mg of ibuprofen within β 10 minutes, and the remaining 400 mg dose was dispensed slowly according 9 to the release characteristics specified in Example 3.

10

11

12 EXAMPLE 5

13

14 78 grams of ibuprofen and 20 grams of hydroxypropylmethylcellulose is having a number average molecular weight of 9,200 grams per mole and a

16 hydroxyl content of 8 wt% and a methoxyl content of 22 wt% were passed

17 through a 40 mesh screen. The resulting sized powders were tumble mixed, ie Anhydrous ethyl alcohol was added slowly to the powders with stirring until a

19 dough consistency was produced. The damp mass was then extruded

20 through a 20 mesh screen and air dried overnight. The resulting dried

21 material was rescreened through a 20 mesh screen to form the final granules

22 2 grams of tabletting lubricant, stearic acid, which had been sized through an

23 80 mesh screen, were then tumbled into the granules.

24

25 513 mg of the resulting granulation was placed in a die cavity having an

26 inside diameter of 9/32 inch and compressed with a deep concave punch

27 tooling using a pressure head of 2 tons, forming a longitudinal capsule having

28 an overall length, including the rounded ends, of 0.543 inch. The cylindrical

29 body of the capsule, from tablet land to tablet land, spanned a distance of 9 0 mm. Each capsule contained a unit dose of drug of 400 mg. Rings of 1 polyethylene having an inside diameter of 9/32, a wall thickness of 0.013 ι inch, and a width of 2 mm were then fabricated. These rings or bands were

2 press fitted onto the capsule to complete the dosage form.

3

4 Drug release studies were performed as described in Example 2. Figures

5 12-15 show the release rates of the ibuprofen cylindrical matrix formulation

6 described above. FIG. 12 shows the release rate of the matrix with no bands.

7 FIG. 13 shows the matrix with two 2 mm bands positioned in the middle of the β matrix with a distance of 2 mm between the bands. FIG. 14 shows the matrix 9 with three 2 mm bands, one positioned in the middle of the capsule and one ιo positioned at each end with a distance of 2 mm between the bands. FIG. 15 ιι shows the matrix with four 2 mm bands, one positioned at each end and two

12 positioned in the middle, each separated by a distance of 0.33 mm.

13

14 As noted in the previous example, the delivery rates shown in FIGs. 12-15 is approach zero order as greater numbers of bands are included. Further, as

16 more of the surface area is covered by the insoluble material, the release rate

17 is prolonged. The total delivery times to dispense 90% of the initial dose are ie as follows: for no bands, 2.3 hours; for two bands, 2.8 hours; for three bands 19 2.8 hours; and for four bands, 3.7 hours.

20

21 EXAMPLE 6

22

23 A 550 mg unit dose for prolonged release of the analgesic drug

24 acetaminophen is prepared as follows. 78 grams of acetaminophen are

25 passed through a sizing screen having 40 wires per inch. 20 grams of a

26 hydroxypropyl methylcellulose having a hydroxypropyl content of 8 wt %, a

27 methoxyl content of 22 wt %, and a number average molecular weight of

28 27,800 grams per mole are passed through a sizing screen with 100 wires

29 per inch. The sized powders are tumble mixed for 5 minutes. Anhydrous

30 ethanol is added to the mixture with stirring until a damp mass is formed. The

31 damp mass is passed through a sizing screen with 20 wires per inch. The ι resulting damp granules are air dried overnight, and then passed again

2 through the 20 mesh sieve. 2 grams of the tabletting lubricant, magnesium

3 stearate are passed through a sizing screen with 80 wires per inch. The

4 sized magnesium stearate is blended into the dried granules to form the final

5 granulation.

6

7 705 mg portions of the final granulation are placed in die cavities having β inside diameters of 0.281 inch. The portions are compressed with deep

9 concave punches under a pressure head of 1 ton, forming longitudinal ιo capsule-shaped tablets.

11

12 The capsules are fed into a Tait Capsealer Machine (Tait Design and i3 Machine Co., Manheim, PA) where three bands are printed onto each

1 capsule. The material forming the bands is a mixture of 50 wt % is ethylcellulose dispersion (Surelease®, Colorcon, West Point, PA) and 50 wt ie % ethyl acrylate methylmethacrylate (Eudragit® NE 30D, RόhmPharma,

17 Weiterstadt, Germany). The bands are applied as an aqueous dispersion ie and the excess water is driven off in a current of warm air. The diameter of

19 the bands is 2 millimeters.

20

21 The above description has been given for ease of understanding only. No

22 unnecessary limitations should be understood therefrom, as modifications will

23 be obvious to those skilled in the art.

24 25 26

Claims

WHAT IS CLAIMED IS:

1. An active agent dosage form for the prolonged delivery of an active agent formulation to a fluid environment of use, the dosage form comprising an active agent formulation matrix with at least two insoluble bands positioned in spaced relationship on the surface of the active agent formulation matrix with the surface of the matrix on both sides of each band exposed to the fluid environment of use.

2. The dosage form of claim 1 wherein the bands are placed on the surface of the active agent formulation matrix.

3. The dosage form of claim 2 wherein the bands drop off as the matrix erodes.

4. The dosage form of claim 1 wherein the bands are printed onto the surface of the active agent formulation matrix.

5. The active agent dosage form of claim 1 wherein the active agent formulation comprises a drug.

6. The active agent dosage form of claim 1 wherein the active agent formulation comprises a drug and the dosage form is administered orally.

7. The active agent dosage form of claim 1 wherein the active agent formulation matrix comprises an active agent formulation and a hydrophilic polymeric material. ι 8. The dosage form of claim 1 wherein the dosage form is

2 cylindrical and the insoluble bands concentrically surround the active agent

3 formulation matrix.

4

5 9. An active agent dosage form for the prolonged delivery of an e active agent formulation to a fluid environment of use, the dosage form

7 comprising: a first active agent formulation matrix and at least two insoluble β bands positioned in spaced relationship on the surface of the first active

9 agent formulation matrix with the surface of the first active agent formulation ιo matrix on both sides of each band exposed to the fluid environment of use, ιι and a second active agent formulation matrix, the first active agent

12 formulation matrix providing for the prolonged delivery of a first active agent

13 and the second active agent formulation matrix providing an initial pulse of a

14 second active agent, the second active agent being the same as or different is than the first active agent.

16

17 10. The active agent dosage form of claim 1 , wherein delivery of the ie active agent formulation lasts for up to about 20 hours.

19

20 11. The active agent dosage form of claim 1 wherein the insoluble

21 bands are between about 0.5 and 8 mm in width.

22

23 12. The active agent dosage form of claim 1 wherein the total

24 number of insoluble bands is between 2 and 10.

25

26 13. A method for making an active agent dosage form for the

27 prolonged release of an active agent to a fluid environment of use, the 2β method comprising:

29 (a) preparing an active agent formulation matrix; and ι (b) applying an insoluble material onto the active agent

2 formulation matrix to form at least two insoluble bands on the surface of the

3 active agent formulation matrix.

4

_#5 14. The method of claim 13 wherein, in step (b), applying the

6 insoluble material is done by printing the insoluble material onto the active

7 agent formulation matrix.

8

9 15. A method for delivering an active agent to a fluid environment of ιo use over a prolonged period of time, said method comprising the steps of: ιι (a) placing an active agent formulation matrix into the fluid

12 environment of use, the matrix having at least two insoluble bands positioned

13 in spaced relationship on its surface with the surface of the active agent

14 formulation matrix on both sides of each band exposed to the fluid is environment of use;

16 (b) allowing the matrix to erode in the fluid environment of

17 use; and is (c) allowing the bands to drop off the matrix and expose the

19 surface of the matrix to the fluid environment of use.

20

21 16. A method for delivering an active agent to a fluid environment of

22 use over a prolonged period of time, said method comprising the steps of:

23 (a) placing an active agent formulation matrix into the fluid

24 environment of use, said matrix having at least two insoluble bands

25 positioned in spaced relationship on its surface with the surface of the active

26 agent formulation matrix on both sides of each band exposed to the fluid

27 environment of use; and

28 (b) allowing the matrix to erode in the fluid environment of

29 use while the bands remain positioned on the surface of the active agent

30 formulation matrix; I-}

ι wherein the surface area of the matrix not covered by the bands

2 increases with time.

3

4 17. A method for delivering a first and second active agent to a fluid

5 environment of use, said method comprising the steps of:

6 (a) placing a first active agent formulation matrix into the

7 fluid environment of use, said matrix comprising a first active agent and β having at least two insoluble bands positioned in spaced relationship on its

9 surface with the surface of the active agent formulation matrix on both sides ιo of each band exposed to the fluid environment of use; ιι (b) placing a second active agent formulation matrix

12 comprising a second active agent into the fluid environment of use;

13 (c) allowing the first active agent formulation matrix to erode

14 in the fluid environment of use to provide prolonged delivery of said first is active agent; and

16 (d) allowing the second active agent matrix to erode in the

17 fluid environment of use to provide an initial pulse of second active agent; ie wherein the first and second active agents may be the same or

19 different.

20

21 18. The method of claim 17 wherein the bands drop off the surface

22 of the first active agent formulation matrix as the matrix erodes in the fluid

23 environment of use.

24

25 19. The method of claim 17 wherein the bands remain positioned on

26 the surface of the first active agent formulation matrix as the matrix erodes in

27 the fluid environment of use.

28 29