Link:  Pharm/Biotech Resources

Title:  Chrono delivery formulations and method of use thereof

United States Patent:  6,926,909

Issued:  August 9, 2005

Inventors:  Mehta; Atul M. (Mahwah, NJ)

Assignee:  Elite Laboratories, Inc. (Northvale, NJ)

Appl. No.:  406961

Filed:  April 4, 2003

A dosage formulation for once daily administration prior to sleeping is described that provides an initial delay in pharmaceutical release followed by controlled release of the pharmaceutical. There is also provided a method for preparing a time specific delayed, controlled release formulation of dosage, which method includes coating a single pellet with at least one dosage layer, which is coated by at least one seal coat and at least one outer rate controlling layer of a water soluble polymer coat. The dosage formulation of this invention provides substantially a drug free interval of about 0 to 5 hours followed by a drug delivery interval at a rate permitting bioavailability thereof for up to about 24 hours following oral administration. A method of using the formulations of the present invention for the treatment of early morning pathologies is also described.

SUMMARY OF THE INVENTION

In a first aspect of the invention there is provided a formulation for administration of a therapeutic agent for treatment of pathologies typically occurring in the morning hours, or upon awakening. The formulation of the present invention is administered once daily prior to sleep and comprises a biologically inert pellet comprising:

wherein release of the drug from the dosage formulation comprises a substantially delayed release followed by sustained release of the drug. In a preferred embodiment, the drug layer is coated with a sealing layer.

In another aspect of the invention there is provided a method of treating, preventing, or controlling hypertension or angina, in a subject in need thereof, which comprises administering to a patient in need of such treatment the dosage formulation of the invention as defined above once daily prior to sleeping.

DETAILED DESCRIPTION OF THE INVENTION

This invention, as disclosed and described herein, provides for a novel time specific delayed release dosage formulation of a therapeutic agent, such as diltiazem, for administration prior to sleeping to treat pathologies that typically occur in the morning hours or upon awakening. This invention provides a dosage formulation that optimizes drug levels at the early morning hours of the dosing period by providing a formulation which exhibits a substantially drug free interval, followed by a drug delivery interval of a period of about 5 to 20 hours following oral administration. Additionally, the dosage formulation, as described herein, provides for a single pellet formulation which requires no mixing and, therefore, permits easy and more accurate manufacturing of the formulation. The dosage formulation of the present invention is referred to herein as a "chrono release" formulation due to its initial time specific delayed release of drug diltiazem, followed by sustained release of drug for up to about 5 to 20 hours following the delayed release, and peaking at about 10 to 12 hours after administration.

The present invention provides a dosage formulation and methods for treating morning pathologies, which include pathologies, diseases, disorders, conditions and clinical symptoms that are typically aggravated or often acute during the last hours of sleeping or upon or shortly after awakening. Most humans sleep for a period of from about 3 to about 8 hours during the night and the pathologies are typically exhibited in the morning. However, some people have altered sleep patterns, sleeping during the day and remaining active during the night. Individuals with such altered sleep patterns may exhibit symptoms or pathologies at night or upon awakening. Therefore, for such people with altered sleep patterns, the methods and formulations of this invention may be administered prior to sleeping, irrespective of actual time of day.

Examples of morning pathologies that may be treated by the formulations and methods of the invention include for example angina, hypertension, arrhythmia, infarction, incontinence, arthritis, Parkinson's disease, and asthma. With each of these disorders, symptoms are usually aggravated or worse during the late night-early morning hours, usually when the person is sleeping or just after the person awakens. The term "sleeping" as used herein means a prolonged period of rest or inactivity or decreased activity. The term "sleep" is used to mean those hours of resting when all clinical stages of sleeping are attained as well as those periods of rest when not all of the clinical stages of sleep are not attained. The term "awaken" refers to the period of arousal from sleeping, which is characterized by an increase in activity. The period of awakening includes the time from arousal from sleep to about four hours thereafter.

The dosage formulations and methods of the present invention are useful for treating the foregoing morning pathologies because the present dosage formulations and methods provide therapeutically effective amounts of drug in a time specific controlled release manner, delivering drug to the blood stream at the time needed most. The once daily, prior to sleep administration of the dosage formulation of the invention provides an alternative to prior art dosage formulations, which require the presence of several core pellets, enteric coating polymers, organic acids and solvents, and extensive mixing of pellets to achieve a once a day effect, and/or do not achieve a sustained and optimal amount of drug at a time when needed most, i.e., in the morning hours or upon awakening.

The present invention provides a novel dosage formulation characterized by having a substantially delayed release followed by controlled and sustained release of the active substance. Substantially delayed release followed by sustained release, as the phrase is defined herein, means maintaining the plasma concentration of drug from about 0 to less than about 20 ng from the time of administration to about 5 hours after administration (a substantially drug free interval), followed by an increase of plasma concentration of drug to a peak concentration of drug at about 8 to about 12 hours after administration of the dosage form. The dosage formulations of this invention afford excellent bioavailability while avoiding fluctuating plasmatic concentration peaks, so that it is now possible to maintain drug plasmatic concentrations in a desired, effective range in a circadian fashion while simplifying the administration of the drug to only once daily.

FIG. 3 (see Original Patent) demonstrates the bioavailability of diltiazem in plasma over a 24 hour period following the administration of a 180 mg diltiazem dosage formulation of the invention. After a 4-5 hour delay following administration, the plasma concentration of the drug substantially and continually increases for about 8-9 hours (peaking at about 10-12 hours after administration of the dosage formulation) and remains at a therapeutically effective level for up to about 20-24 hours following administration. In the case of the diltiazem formulation of the invention containing a dosage of 180 mg diltiazem, the plasma concentration of drug in the blood remains at less than about 20 ng/ml for up to about 5 hours after administration and then increases to a peak concentration of from about 90 to about 120 ng/ml in a sustained and controlled manner.

According to the present invention, the time specific delayed release dosage formulation is characterized by having a biologically inert pellet coated by at least one layer of drug(s) in admixture with a suitable binder agent; which is coated with an outer layer referred to herein as "the rate controlling layer".

In one embodiment of the invention, the drug contained in the drug layer of the pellets is useful for treating myocardial or cerebral infarction. In this embodiment, the pellets may contain a coating of a therapeutically effective amount of diltiazem or a pharmaceutically acceptable salt thereof, or any other drug alone or in combination with diltiazem that is useful in treating infarctions. For example, the pellets may contain an anticoagulant or antiplatelet agent, such as for example, warfarin, acetylsalicylic acid, ticlopidine and the like, alone or in combination with diltiazem. In the case of diltiazem, the pharmaceutically acceptable salts may include the hydrochloride, sulfate or phosphate salts. However, they may also include the acetate, citrate or lactate salts, for example. It is preferred however, that the hydrochloride salt of diltiazem be used.

For treatment of angina, the pellets may contain a coating of a therapeutically effective amount of an antiangina agent such as isosorbide dinitrate or isosorbate mononitrate. For treatment of hypertension or arrhythmia the pellets may contain, alone or in combination, a therapeutically effective amount of calcium antagonists, angiotensin-converting enzyme inhibitors, beta-blockers, any of alpha-antagonists, and the like.

For the treatment of other pathologies, such as incontinence, the pellets may contain a therapeutically effective amount of an anticholinergic or antispasmodic agent or a vasopressin analogue for example. For the treatment of arthritis, the pellets may contain a therapeutically effective amount of an antiarthritis agent such as non-steroidal antiinflammatory agents, such as diclofenac, ketoprofen, ibuprofen, mesalamine, sulfides, and the like, as well as their pharmaceutically acceptable salts.

The drug layer is applied to biologically inert pharmaceutically acceptable pellets in admixture with a suitable binder agent. Many types of pellets that are suitable for use in the methods and formulations of the present invention are commercially available from a number of pharmaceutical supply companies; for example, non-pareils, sugar and/or starch-based pellets. Non-pareil pellets of particle size 25 to 30 mesh are particularly preferred, although any non-pareil pellet of mesh size within the range of 14 mesh to 60 mesh are also preferred for use in this invention.

Suitable binder agents for use in the drug layer of the coated pellets of the present invention include, for example, water soluble polymers such as hydroxypropylmethyl cellulose (3 to 6 cps, preferably 6 cps), hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone and the like. Preferably, hydroxypropylmethyl cellulose, and most preferably, hydroxypropylmethyl cellulose-E-6 is used in the practice of the present invention. Preferably the amount of binder agent included in the drug layer is in a ratio of binder agent to drug of from about 0.5:20, preferably about 0.7:10, most preferably about 1:8. The drug layer may also contain a suitable carrier or diluent, and may optionally contain a surfactant.

In a preferred embodiment, the drug layer is coated with an optional sealing layer. The sealing layer contains a water soluble polymer, which may be the same or different from the binder agent present in the drug layer. For example, the sealing agent may include a water soluble polymer such as hydroxypropylmethyl cellulose (3 to 6 cps, preferably 6 cps), hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone and the like. Preferably, hydroxypropyl-methyl cellulose, and most preferably, hydroxypropylmethyl cellulose-E-6 is used in the sealing layer.

The total amount of optional sealing layer contained in the pharmaceutical loaded pellets may be varied depending on the desired release rate of the pharmaceutical agent, e.g., diltiazem-HCl. When the pharmaceutical agent of the pellets is diltiazem, it is preferred that the polymer coating comprise about 0.5% to about 5% of the total weight of the pellet, and most preferably, about 1% to about 2% of the total weight of the pellet.

The outer rate controlling layer contains a water insoluble polymer, which may be ethyl cellulose, a copolymer of acrylic and methylacrylic acid esters, which is physiologically acceptable, water insoluble, and permeable to the release of drug contained in the drug layer. Suitable water insoluble polymers include for example, Eudragit RL 30 D, Eudragit RS 30 D, or a poly(meth)acrylate polymer, such as Eudragit NE 30 D, and Eudragit NE 40 D, or a combination thereof. Most preferably, the poly(meth)acrylate polymer, Eudragit NE 30 D, is used in formulating the controlled release coating. Eudragit NE 30 D, Eudragit RS 30 D and Eudragit RL 30 D polymers are available from Rhom Pharma, D-6108 Weiterstadt 1, Dr. Otto-Rohm-Str. 2-4, Germany. Eudragit NE 30 D and Eudragit NE 40 D are pH independent polymers available as a 30% or 40% aqueous dispersion. Eudragit RS 30 D and Eudragit RL 30 D are available as aqueous dispersions containing 30% dry substances.

In a preferred embodiment of the invention the binder agent in the drug layer and the innermost drug sealing layer is hydroxypropylmethyl cellulose and the outer rate controlling layer is Eudragit NE 30 D.

The outer rate controlling layer is prepared as a dispersion and may be mixed with a suspension of lubricant agent, such as calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc or a combination thereof to form the time specific controlled release coating mixture. In particular, it is preferred that the outer rate controlling layer contains an amount of magnesium stearate sufficient to provide delayed release of diltiazem for up to about 4-5 hours after administration. In a most preferred embodiment the outer rate controlling layer contains a combination of magnesium stearate admixed with Eudragit NE 30 and may contain simethicone. The final, dried controlled release coating contains about 2% to 10% magnesium stearate or other lubricant, and more preferably about 2.5% to 5.5%, and most preferably about 2.5% to 3.0% magnesium stearate or other lubricant based on the total weight of solids content of the controlled release formulation. The lubricant functions to prevent agglomeration of the coated pellets during processing and also helps to delay release of the pharmaceutical agent from the coated pellets. The presence of an amount of about 2.5% to 3.0% w/w magnesium stearate or other lubricant in the controlled release coating affects the delayed release of the drug for about 4-5 hours following oral administration of the formulation.

In another embodiment of the invention the outer rate controlling layer is coated with an enteric coating polymer, which may also contain a plasticizer. A preferred enteric coating polymer is Eudragit L 30 D. Suitable plasticizers for inclusion in the enteric layer include, for example, triethyl citrate, polyethylene glycol, dibutyl phthalate, diethylphthalate and triacetin. The optional enteric coating, which is pH dependant and resistant to gastric fluids may comprise from about 4 to 10%, preferably about 4 to 6% of the total weight of the diltiazem formulation. The enteric coating may also be coated with one or more layers of a sealant or a binding agent.

The drug layer, optional sealing layer, outer rate controlling layer, and optional enteric coating may each further comprise diluents, carriers, fillers and other pharmaceutical additives which may affect the rate of release of active agent(s) from the pellet. For example, the outer rate controlling layer preferably contains a lubricant agent and preferably, the drug layer contains a surfactant. The pellet layers may further contain pharmaceutically acceptable excipients such as anti-adherents, pharmaceutically acceptable pigment such as, titanium dioxide, iron oxide and various color pigments including vegetable dyes, and the like. Preferably, the pharmaceutical loaded pellets of the invention provide in total a potency of approximately 50% (w/w) based upon the total weight of the layered pellets, although the potency can be adjusted as desired. When the pharmaceutical agent included in the layering is diltiazem, it is preferred that the pellet be formulated at about 45 to about 55% potency (w/w) However, the skilled practitioner can make the present dosage formulation at any desired drug potency.

The time specific delayed release formulation, as disclosed herein, permits the release of the drug in a manner to provide and maintain a therapeutic amount of diltiazem in circulation for about 15-24 hours after administration of the formulation, following an approximately 4-5 hour initial delay in drug release. In particular, the delayed release followed by sustained release formulation described herein, when administered prior to sleeping provides optimal concentration of drug when most needed, i.e., in the morning hours or upon awakening.

The process for making the pharmaceutical formulations of the present invention includes coating at least one layer of drug(s) and suitable binder agent onto the surface of a biologically inert pellet; i.e., layered or a non-pareil pellet (sugar and/or starch-based pellets) to form drug loaded pellets. The drug loaded pellets are then optionally enveloped by a sealing layer. The drug loaded pellets (with or without a sealing layer) are finally coated with an outer rate controlling layer. Optionally, the outer controlled release layer may be coated with a sealing layer and/or enteric coating layer.

In preparing the formulations of the invention, the drug layer may be applied by spraying the drug/binder agent solution onto non-pareil or other pellets that have been suspended in a fluidized bed, for example. Other conventional techniques such as pan coating or extruder/marumerizer can also be used. After the pellets are coated with the drug layer they may optionally be dried by air exposure, or other methods known in the art (although drying may occur spontaneously from air flow in the fluid bed processor). Pellets obtained from the drug layering are then optionally fluidized and sprayed with the water soluble, water permeable, and pharmaceutically acceptable polymer coating to form the innermost sealing layer.

Preferably, the sealing agent is dissolved in water to form a 5% to 30% (w/w) solution, preferably a 7% to 25% (w/w) solution and most preferably, an approximately 10% (w/w) solution. The solution of sealing agent is then sprayed onto the pellet using, for example, a fluid processor. The ratio of sealing agent to total weight of the dosage formulation is about 0.5% to about 5%, more preferably from 1% to about 3% (w/w), and most preferably about 2%.

The rate controlling polymer is layered onto the drug loaded and optionally sealed pellets. The polymer comprising the outer rate controlling layer is generally prepared as a dispersion and sprayed onto the prepared pellets. The total amount of rate controlling polymer in the pellets is in the range of from about 5-12% of the total weight of the prepared pellets, preferably about 7-9% of the total weight of the prepared pellets. By varying the amount of rate controlling polymer within this range, a desired predetermined delay followed by sustained release of the therapeutic agent is achieved.

At the final stage the pellets may be subjected to a curing process. The pellets are cured at a temperature in the range of from about 30° to about 50° C., preferably, from about 35° to about 45° C., and most preferably, about 40° C. for a period of about 5 to about 10 days and, preferably, about 7 days. Surprisingly, although others in the art have found shorter curing times to be preferred, the inventor of this invention has found that these long curing times help to stabilize the release of pharmaceutical agent from the pellets even after long storage periods.

The cured coated pellets may be weighed out according to the total dose of pharmaceutical agent to be administered to patients. Diluent may be added, such as, for example, dextrose, sorbitol, mannitol, microcrystalline cellulose, methocel ether, lactose, glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, and combinations thereof, among other commonly used pharmaceutical diluents, and the mixture of coated pellets and diluents pressed into tablets. Alternatively, the mixture of the coated pellets alone or with tale can be encapsulated in a capsule, such as a hard gelatin capsule.

It is often desirable to add inert diluent when formulating the coated pellets into tablet form. The presence of pharmaceutical diluents, such as microcrystalline cellulose, methocel ether, glyceryl palmitostearate, glyceryl stearate, and/or glyceryl behemate, for example, in the pellet mixture serves to cushion the pellets so that they are not significantly ruptured during compression.

In general, the release rate of pharmaceutical agent from the pellets is dependent upon a number of factors including, inter alia, the overall structure and design of the layered pellet, the potency of the layered pellet, the type and amount of polymer present in each of the drug layer, optional sealing layer and outermost layer. The pellets may be formulated into tablets or encapsulated in the desired dosage amount. Typical unit dosage amounts for a once before sleep delayed release tablet for oral administration include any dosage between about 25 and 1000 mg, such as 50, 100, 200, 300, 500, 750 mg.

The dosage formulations of the invention are formulated to provide a sustained release of drug following a predetermined delay in drug release. Preferably, the dosage formulations of the invention provide a release of drug when measured in an aqueous solution in a paddle apparatus according to U.S. Pharmacopeia XXII, that corresponds to the following dissolution profile:

1) from 0 to about 8% release of total drug from 0 to about 5 hours (a substantially drug-free interval);

2) from about 8% to about 90% release of total drug from about 5 to about 15 hours; and

3) release of substantially all of the remaining drug (about 90% to about 100%) from the pellets during the period from 15 hours to 24 hours. It is not necessary that all of the remaining diltiazem is released from the formulation.

The release profile of diltiazem from the formulations of the present invention ensures that after once daily (prior to sleeping) administration of the present dosage formulation a therapeutically effective amount of drug is available in the patient's plasma in the morning hours or upon awakening to treat morning pathologies, such as myocardial infarction.

Claim 1 of 21 Claims

1. A method of preventing, treating or controlling hypertension or angina, or the symptoms thereof, in a subject in need thereof, comprising:

orally administering to said subject once prior to sleep a dosage formulation comprising

a biologically inert pellet;

a drug layer coating the biologically inert pellet, said drug layer comprising a dosage form of a pharmaceutical agent and a binder agent, said binder agent and said pharmaceutical agent being present in a ratio of about 0.5:20; and

an outer rate controlling layer coating the drug layer, said outer rate controlling layer comprising a water insoluble polymer, said water insoluble polymer being present in a total amount in the range of from about 5-12% of the total weight of the dosage formulation;

wherein release of the pharmaceutical agent from the dosage formulation in vitro substantially corresponds to the following dissolution profile, as measured in water in a paddle apparatus according to U.S. Pharmacopeia XXII at 100 rpm:

a) not more than about 8% of the pharmaceutical agent is released at about 5 hours from the time of the administration of the dosage formulation; and

b) about 90% of the pharmaceutical agent is released at about 15 hours from the time of the administration of the dosage formulation.

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