The invention is directed to a drug delivery device for controlled release of a drug, comprising a core that has a cylindrical plug embedded therein; and a coating that at least partially surrounds the core. The core is comprised of a drug and excipients. The coating surrounding the core is essentially impermeable to the drug. The cylindrical plug, which is embedded in the core, may be hollow or solid. The drug delivery device enables zero-order drug release profiles as well as more complicated release profiles to be obtained. The invention is also directed to a method of making the drug delivery device.

SUMMARY OF THE INVENTION

The invention is directed to a drug delivery device, comprising a core that has a cylindrical plug embedded therein; and a coating that at least partially surrounds the core. The core is comprised of a drug and excipients. The coating surrounding the core is essentially impermeable to the drug. The cylindrical plug, which is embedded in the core, may be hollow or solid.

The cylindrical plug expands upon absorbing the little water that permeates the coating, punching a hole in the impermeable coating. The hole that is formed is the size of the diameter of the solid cylindrical plug or the inner diameter of the hollow cylindrical plug. Thus, the hole is a macroscopic hole. The hole in the coating is filled with either the solid cylindrical plug or the hollow cylindrical plug. In the case of a solid cylindrical plug, water permeates into the cylindrical plug and drug permeates out of the cylindrical plug. Thus, drug release is very slow up until the point when the cylindrical plug falls out of the delivery device, as described below. In the case of a hollow cylindrical plug, drug release is effected by entry of water through the macroscopic hole to the core, causing drug dissolution or erosion and the exit of the drug solution or drug suspension through the same hole.

Drug dissolution or erosion is designed to be the rate determining step of drug release and is constant because of the constant cross section of the hole formed in the coating. In this way, the release of drug occurs at a constant, i.e., zero-order release, rate. The properties of the materials of which the cylindrical plug is made (i.e. how much axial swelling there is), as well as the geometry of the cylindrical plug, determine the size of the macroscopic hole and thus the rate of the zero order drug release. Changes in the rate of dissolution or erosion of the drug core can also effect the rate of drug release. Thus, it is also possible to obtain non-zero order release profiles, if so desired.

Non-zero order release profiles are easily attainable with the drug delivery device of the invention. Release delays may be obtained by coating the drug delivery device with an outer enteric coating. The enteric coating is applied over the impermeable coating in a smooth fashion. Release delays may also be obtained by varying the thickness of the impermeable coating. A thicker coating will delay the swelling of the cylindrical plug, thereby delaying drug release. The size of the cylindrical plug, and the nature of the excipients used to form the cylindrical plug, determines the rate of drug delivery from the drug delivery device and whether it provides a descending, ascending or zero order drug release profile. For example, once the cylindrical plug has burst through the coating, if the cylindrical plug continues to swell thereby making the diameter of the hollow cylindrical plug smaller with time, then a descending release profile will be observed. If, after the cylindrical plug bursts through the coating, it erodes or dissolves thereby making the diameter of the hole larger with time, then an ascending release profile will be observed. And, if after the cylindrical plug bursts through the coating and maintains its integrity, then a zero-order release profile will be observed.

Abrupt changes in the rate of drug release after a predetermined time can be brought about by having the cylindrical plug designed to fall out of the core after a certain period. The orifice of drug release will then grow considerably, allowing a more rapid drug release or a burst release to be appended to an extended zero order drug release profile. For example, if the outer diameter of the hollow cylindrical plug is 6 mm and the inner diameter is 3 mm, then the cross sectional area will grow four fold upon the plug falling out of the system. It is also possible to delay the release of drug by using a solid cylindrical plug. In which case, drug release is very slow or almost zero until the solid cylindrical plug falls out of the delivery device.

The drug delivery device may be made by forming a core comprising a drug and excipients, and embedding a cylindrical plug in the core. (FIG. 1). The core is then at least partially coated with a membrane that is essentially impermeable to the drug. This membrane serves to prevent any significant drug release from the surface of the drug delivery device. Small amounts of water do permeate the membrane causing the cylindrical plug to swell and burst the surface of the membrane. The result is a partially plugged hole of a defined geometry (FIG. 2). This hole is not a microscopic hole as in the osmotic pump systems. It is a macroscopic hole and its diameter is defined by the inner diameter of the hollow cylindrical plug or the diameter of the solid cylindrical plug. Water enters through the hole and dissolves drug from the core or erodes the core along with drug. The drug flows out of the system through the channel left in the cylindrical plug. As the drug delivery progresses a void may be formed in the core. This void will be filled with a pool of drug. The rate of drug release is, however, still controlled by the orifice (FIG. 3).

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a drug delivery device for controlled release of the drug, comprising a drug core and a cylindrical plug embedded in the core. The core is at least partially coated with a coating which is essentially impermeable to the drug. The impermeable coating may be coated with a drug coating.

The core may be a standard pharmaceutical non-expanding core designed to dissolve or erode at a rate that is desired for the therapy at hand. Standard pharmaceutical excipients, such as, fillers, binders, diluents, disintegrants, lubricants, and wetting agents, may be used to form the core. Useful excipients include, but are not limited to, Nutab.TM. (sucrose), Polyethylene glycols (PEG), Microcrystalline cellulose, lactose, sodium lauryl sulfate, polyvinylpyrrolidone and mixtures thereof. One preferred composition of the core is: 53.9 wt. % Nutab.TM., 29 wt. % PEG 8000, 15 wt. % Avicel pH102.TM. (Microcrystalline cellulose), 1.1 wt. % Acetaminophen and 1 wt. % magnesium stearate. The diameter of the core preferably ranges from about 7 mm to about 15 mm, with about 9 to about 11 mm being more preferred. The drug content of the core can be from 0.1 to 99% by weight of the core, and the drug delivery device can be used to deliver essentially any drug for which oral administration is desired. Preferred drugs include acetaminophen, methylphenidate, oxybutynin, tizanidine and copaxone.

The cylindrical plug, which is preferably embedded at the surface of the core, may be solid or hollow. When the cylindrical plug is hollow, its outer diameter preferably ranges from about 5 to about 9 mm, with about 7 mm being more preferred. The inner diameter ranges from about 1 mm to about 6 mm, with about 2 mm to about 3 mm being most preferred for an outer diameter of about 7 mm. The cylindrical plug may be comprised of a material that further swells after the initial swelling or a material that erodes or dissolves upon contact with fluid after the initial swelling. The cylindrical plug may be in the form of a bi-layer tablet. One of the layers may be a placebo layer and the other layer may be a drug layer. Alternately, both layers may contain a drug. The drug in the cylindrical plug may be the same or different as that in the core. Additionally, each layer may contain a different drug.

Preferably, the excipients that form the cylindrical plug are excipients that can expand rapidly to break through the impermeable coating while keeping the form and shape of the cylindrical plug. Preferably, the cylindrical plug is comprised of a hydrogel. Examples of hydrogels which may be used to form the cylindrical plug include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene oxide, and mixtures thereof. Preferably, the cylindrical plug is further comprised of a superdisintegrant. Examples of superdisintegrants which may be used include croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof.

One preferred formulation of the cylindrical plug is: Hydroxypropylcellulose (Klucel MF) 35 wt. %, Methylcellulose 1500 34 wt. %, Crosscarmelose sodium 30 wt. % and Magnesium stearate 1 wt. %. Crosscarmellose sodium, which is a super disintegrant, serves to cause rapid swelling, while the hydrogel components prevent disintegration of the tablet and keep its geometric integrity.

Other excipients known in the art to posess these properties may be substituted for the preferred formulation as long as they serve to achieve the same function. Any superdisintegrant (e.g. crospovidone, sodium starch glycolate) may be substituted for the crosscarmelose and many combinations of hydrogel excipients chosen from the many grades of hydroxypropylcellulose, hydroxpropylmethylcellulose, polyvinylpyrollidone and other polysaccharides may be used. One versed in the art will know how to change the formulation to achieve more or less swelling, or more or less dissolution of the cylindrical plug during the drug release time.

The core containing the embedded cylindrical plug is coated with a coating which is essentially impermeable to the drug. The impermeable coating is preferably plasticized to a level that facilitates smooth coating but leaves the coat sufficiently rigid so that it bursts neatly. Examples of plasticizers that may be used include include triethylcitrate and polyethylene glycols. The grade of polymer and the amount of plasticizer can be determined by one skilled in the art by routine experimentation. Higher molecular weight polymers will need more plasticizer to keep them in the useful range of rigidity/plasticity. Typically, the plasticizer is present in an amount of from about 5 40 by weight of the polymer. A preferred coating comprises ethylcellulose having viscosity of 7 cps, plasticized with about 20% by weight of triethylcitrate. Another preferred coating comprises ethylcellulose having a viscosity of 7 cps plasticized with about 20% by weight of polyethylene glycol (PEG) 1000.

In a further embodiment, the impermeable coating may be coated with a drug coating. The drug coating may be one that dissolves quickly to provide an immediate pulse of the drug. Alternately, the drug coating may be one that erodes to provide a sustained release of the drug. The drug in the drug coating may be the same or different from the drug in the core. An example of a drug coating that dissolves quickly is one comprising Eudragit E (which dissolves readily in the stomach). An example of an eroding drug coating is one that comprises various grades of polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropylmethylcellulose, optionally including a plasticizer(s) known in the art.

In another embodiment the cylindrical plug can contain a dose of the same or a different drug as that in the core. This dose can be designed to be delivered slowly from the cylindrical plug by diffusion or erosion. This delivery device can also be further coated with a drug coating as described above.

In another embodiment, the solid cylinder is a bilayer tablet, where one layer expands upon absorbing moisture and bursts through the impermeable coating, while the second layer releases a drug (which can be the same or different as that in the core). The drug may be released in a delayed fashion, the delay being the time needed for the bi-layer tablet to burst the impermeable coating. Or the drug may be released in a sustained fashion. This delivery device can also be further coated with a drug coating as described above.

In a preferred embodiment, methylphenidate is incorporated into the core. The core is comprised of about: 1 10 wt. % drug; 1 20 wt. % microcrystalline cellulose; 60 90 wt % sucrose; and 0.2 2 wt. % of a lubricant, such as magnesium stearate. The core has a solid cylindrical plug embedded therein. The solid cylindrical plug is in the form of a bi-layer tablet. One of the layers comprises about: 1 30 wt. % methylphenidate; 60 95 wt. % lactose; 0 5 wt. % microcrystalline cellulose; and 0.2 2 wt. % lubricant. The other layer, which is the expanding layer that bursts through the impermeable coating, comprises about: 20 50 wt. % hydroxypropylcellulose HF, 20 50 wt. % methylcellulose 1500, 25 40 wt. % croscarmellose sodium and 0.2 1 wt. % lubricant. The cylindrical plug is pressed into the surface of the core and the ensemble is coated with an impermeable coating. The impermeable coating is comprised of about 5 10 mg per tablet of ethylcellulose (Ethocel 7 cps) plasticized with about 20 wt. % triethylcitrate. The impermeable coating is then overcoated with a coat comprising Eudragit E and 0 50 wt. % methylphenidate. Thus, this drug delivery device provides three different doses of methylphenidate. The first dose is an immediate release dose from the outermost (Eudragit E) coat. The second dose is a short controlled release dose (one to two hours in duration). The third dose is an extended release dose from the core after the solid cylindrical plug has fallen out. This dose lasts for about 8 12 hours.

In a more preferred embodiment, the core comprises about: 7 wt. % methylphenidate; 10 wt. % microcrystalline cellulose; 82 wt. % sucrose; and 1 wt. % magnesium stearate. The cylindrical plug is a bi-layer tablet, wherein one of the layers is a drug layer and the other layer is an expanding layer. The drug layer weighs about 35 mg and comprises about: 24 wt. % methylphenidate; 70 wt. % lactose; 5 wt. % microcrystalline cellulose; and 1 wt. % magnesium stearate. The expanding layer weighs about 45 mg and comprises about: 35 wt. % hydroxypropylcellulose HF, 34 wt. % methylcellulose 1500; 30 wt. % croscarmellose sodium; and 1 wt. % magnesium stearate. The cylindrical plug, which has a diameter of about 5 mm, is pressed into the surface of the core and the ensemble is coated with an impermeable coating comprised of about 8 mg per tablet of ethylcellulose (Ethocel 7 cps) plasticized with about 20 wt. % triethylcitrate. This impermeable coating is then over coated with about 18 mg of a drug layer comprised of about: 67 wt. % Eudragit E and 33 wt. % methylphenidate. The entire drug delivery device is an 8 mm tablet weighing about 425 mg.

In yet another embodiment, the core can be a bilayer tablet, wherein each layer contains the same or different drug. Alternately, the upper layer can be a placebo layer to provide either a delay before drug delivery (in the case of the placebo layer) or sequential delivery of two different drugs with independent release profiles or two different release profiles of the same drug.

In a preferred embodiment, a drug may be incorporated into the lower layer of the core, while the other layer comprises a slowly eroding placebo formulation. The drug layer provides a delayed dose of the drug and may be a slow release zero order formulation or may be of short duration slow release so that it approximates a drug burst. The cylindrical plug is a solid cylindrical plug comprised of a placebo formulation. A first dose of drug is provided by coating the impermeable coat with a drug containing overcoat.

In a more preferred embodiment, the core is comprised of two layers. The lower layer comprises about 2 to about 36 mg tizanidine. This layer may be formulated to release the drug in a sustained or immediate fashion. The upper layer comprises excipients that are eroded slowly over several hours. For example, the upper layer may comprise sucrose, polyvinylpyrrolidone K-30, lactose and similar excipients.

In a most preferred embodiment, the core has two layers: the upper layer weighs about 210 mg and comprises about 89 wt. % sucrose, about 10 wt. % polyvinylpyrrolidone, and about 1 wt. % magnesium stearate; and the lower layer contains tizanidine and excipients. The solid cylindrical plug is about 5 mm in diameter and weighs about 50 mg. The cylindrical plug comprises about 37 wt. % hydroxypropylcellulose HF, about 34 wt. % methylcellulose 1500, about 28 wt. % croscarmellose sodium and about 1 wt. % magnesium stearate. The solid cylindrical plug is pressed into the upper layer of the core and the entire ensemble is coated first with an impermeable coat of ethylcellulose and then with an overcoat comprised of Eudragit E and about 2 to 8 mg tizanidine. The drug overcoat dissolves readily in gastric fluid giving an immediate burst of tizanidine. The second dose of tizanidine is delayed several hours before it is delivered.

Thus, the drug delivery device is capable of providing various release profiles, including a zero order drug release profile, a biphasic drug release profile, a triphasic drug release profile, an ascending drug release profile, or a descending drug release profile.

The invention further provides a method of making a drug delivery device by forming a core comprised of a drug and excipients; embedding a cylindrical plug in the core; and at least partially coating the core with a coating which is essentially impermeable to the drug.

The cylindrical plug may be formed using standard tableting machines with a punch of proper design. It may be formed by direct compression or standard granulation techniques. The cylindrical plug may be comprised of two layers. One of the layers may be a placebo layer and the other layer may be a drug layer. Alternately, both layers may contain a drug. The drug in the cylindrical plug may be the same or different as that in the core. Additionally, each layer may contain a different drug.

The core, with the cylindrical plug embedded therein, may be produced in a standard press coat tableting machine (e.g. Killian RUD or equivalents). The cylindrical plug is fed as a preformed plug and the core formulation is fed as a mixture of powders or as a granulate. The press coat tableting machine is operated with the inner tablet off center to place it at the surface of the core. The entire assembly is coated with an impermeable coating such as ethylcellulose or Eudragit RS.

In one embodiment, the core is a bi-layer tablet where the lower layer is the drug containing layer and the upper layer is a placebo layer. The cylindrical plug is embedded at the surface of the upper layer. In this embodiment, the core is produced in a press coating tableting machine (Kilian RUD) modified to have two powder adding stations before the tablet adding station (so that the tablet is at the surface and not in the center of the tablet as in a "press coated" tablet) and fitted with normal concave punches. The lower layer is formed by blending the drug and excipients and filling the mixture into the die at the first fill station. The upper layer is formed by blending the appropriate excipients and feeding the mixture at the second station. The delay in the release of the drug in the lower layer can be controlled by adding more or less of the mixture which forms the upper placeble layer to the second fill station. The cylindrical plug is then fed as a preformed tablet at the third station using the Kilian RUD automatic mechanism for adding preformed tablets to the powder bed.
 

Claim 1 of 44 Claims

1. A drug delivery device, comprising: a core comprising a drug; a cylindrical plug embedded in the core, wherein said cylindrical plug comprises a swellable material; and a coating at least partially surrounding the core and covering the plug, wherein said coating is essentially impermeable to the drug, and said plug punctures said coating upon swelling of said plug, thereby forming an orifice in said coating.

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