CA2718639A1 - Methylphenidate extended release therapeutic drug delivery system - Google Patents
Methylphenidate extended release therapeutic drug delivery system Download PDFInfo
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- CA2718639A1 CA2718639A1 CA2718639A CA2718639A CA2718639A1 CA 2718639 A1 CA2718639 A1 CA 2718639A1 CA 2718639 A CA2718639 A CA 2718639A CA 2718639 A CA2718639 A CA 2718639A CA 2718639 A1 CA2718639 A1 CA 2718639A1
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- therapeutic drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
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Abstract
The present invention relates to an extended release therapeutic drug delivery system comprising a controlled release core matrix composition comprising an active pharmaceutical ingredient such as a central nervous system stimulant (e.g., methylphenidate) and a release controlling agent (i.e., HPMC -K4M, HPMC-K I00M CR or HPMC-K 15 M CR) as well as a controlled release coating layer composition covering the core matrix composition, which comprises controlled release polymers such as Eudragit RL 30D. The extended release therapeutic drug delivery system is for use once or twice daily administration. The present invention also relates to processes for manufacturing such an extended release therapeutic drug delivery system.
Description
METHYLPHENIDATE EXTENDED RELEASE
THERAPEUTIC DRUG DELIVERY SYSTEM
FIELD OF THE INVENTION
The present invention relates to an extended release therapeutic drug delivery system, a process for manufacturing same, as well as the composition of the dosage form. In particular, the present invention relates to an extended release therapeutic drug delivery system comprising methylphenidate as a pharmaceutically acceptable active ingredient.
BACKGROUND OF THE INVENTION
Methylphenidate (CAS [113-45-11), a piperidine derivative, is chemically designated as a-phenyl-2-piperidine-acetic acid methyl ester; methyl phenidylacetate; methyl a-phenyl- a-(2-piperydl) acetate; methylphenidan, and whereas methylphenidate hydrochloride (CAS [298-59-9]), a mild central nervous system (CNS) stimulant, C14H19NO2 = HCI, is chemically designated as methyl a-phenyl-2-piperidineacetate hydrochloride. Its structural formula is o 0 H
N = HCI
Methylphenidate hydrochloride is known under various brand names, such as Ciba 4311/B, Centedrin , Concerta , Equasym ; Metadate and Ritalin . This compound is available in various forms of tablets, including 5, 10, and 20 mg tablets for oral administration, as well as sustained-release tablets of 20 mg for oral administration (for example Ritalin-SR).
Methylphenidate hydrochloride (HC1) is used in the treatment of Attention Deficit Disorder ("ADD"), a commonly diagnosed nervous system illness in children that is characterized by both distractibility and impulsivity. Methylphenidate HCl is also used to treat a related disorder, Attention Deficit Hyperactivity Disorder
THERAPEUTIC DRUG DELIVERY SYSTEM
FIELD OF THE INVENTION
The present invention relates to an extended release therapeutic drug delivery system, a process for manufacturing same, as well as the composition of the dosage form. In particular, the present invention relates to an extended release therapeutic drug delivery system comprising methylphenidate as a pharmaceutically acceptable active ingredient.
BACKGROUND OF THE INVENTION
Methylphenidate (CAS [113-45-11), a piperidine derivative, is chemically designated as a-phenyl-2-piperidine-acetic acid methyl ester; methyl phenidylacetate; methyl a-phenyl- a-(2-piperydl) acetate; methylphenidan, and whereas methylphenidate hydrochloride (CAS [298-59-9]), a mild central nervous system (CNS) stimulant, C14H19NO2 = HCI, is chemically designated as methyl a-phenyl-2-piperidineacetate hydrochloride. Its structural formula is o 0 H
N = HCI
Methylphenidate hydrochloride is known under various brand names, such as Ciba 4311/B, Centedrin , Concerta , Equasym ; Metadate and Ritalin . This compound is available in various forms of tablets, including 5, 10, and 20 mg tablets for oral administration, as well as sustained-release tablets of 20 mg for oral administration (for example Ritalin-SR).
Methylphenidate hydrochloride (HC1) is used in the treatment of Attention Deficit Disorder ("ADD"), a commonly diagnosed nervous system illness in children that is characterized by both distractibility and impulsivity. Methylphenidate HCl is also used to treat a related disorder, Attention Deficit Hyperactivity Disorder
2 ("ADHD"), in which symptoms of hyperactivity are present along with the symptoms of ADD. The drug is additionally used in the symptomatic treatment of narcolepsy, depression, the cognitive decline associated with Acquired Immunodeficiency Syndrome ("AIDS") or AIDS-related conditions, as well as for mood elevation, particularly in terminally ill patients with diseases such as cancer.
The preparation of methylphenidate is described in L. Panizzon, Heiv. Chim.
Acta, 27, 1748 (1944), M. Hartmann, L. Panizzon and in U.S. Patent No.
2,507,631 (issued 1950 to Ciba Pharmaceutical Products Inc.).
Many formulations or dosage forms containing methylphenidate HCl have been reported. For example, Concerta is currently marketed as a tablet containing three layers in which is found methylphenidate hydrochloride (it is a tri-layer capsule shaped tablet). The tablet contains three inner layers and a push layer to help release the drug from the system and a drug overcoat layer. The coating layer has holes which are made by laser, these holes form the controlled release mechanism for the methylphenidate contained in this dosage form. This design allows the controlled release of the drug in a unique and precise pattern.
Canadian Patent No. 2,264,852 (Gupta et al.) is directed to the use of a composition comprising 100 ng to 500 mg methylphenidate or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, the composition releasing methylphenidate, or a pharmaceutically acceptable salt, thereof in a sustained-ascending dose over time, for regulation of tolerance to methylphenidate or a pharmaceutically acceptable salt thereof.
Canadian Patent Application No. 2,426,883 (Bettman et al.) (equivalent to U.S.
Patent No. 6,344,215) is directed to a pharmaceutical modified release (MR) methylphenidate dosage form, such as a capsule of methylphenidate indicated for the treatment of children with ADHD, capable of delivering a portion of the dose for rapid onset of action and the remainder of the dose in a controlled manner for about 12 hours. The dosage form is composed of a multitude of multicoated particles
The preparation of methylphenidate is described in L. Panizzon, Heiv. Chim.
Acta, 27, 1748 (1944), M. Hartmann, L. Panizzon and in U.S. Patent No.
2,507,631 (issued 1950 to Ciba Pharmaceutical Products Inc.).
Many formulations or dosage forms containing methylphenidate HCl have been reported. For example, Concerta is currently marketed as a tablet containing three layers in which is found methylphenidate hydrochloride (it is a tri-layer capsule shaped tablet). The tablet contains three inner layers and a push layer to help release the drug from the system and a drug overcoat layer. The coating layer has holes which are made by laser, these holes form the controlled release mechanism for the methylphenidate contained in this dosage form. This design allows the controlled release of the drug in a unique and precise pattern.
Canadian Patent No. 2,264,852 (Gupta et al.) is directed to the use of a composition comprising 100 ng to 500 mg methylphenidate or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, the composition releasing methylphenidate, or a pharmaceutically acceptable salt, thereof in a sustained-ascending dose over time, for regulation of tolerance to methylphenidate or a pharmaceutically acceptable salt thereof.
Canadian Patent Application No. 2,426,883 (Bettman et al.) (equivalent to U.S.
Patent No. 6,344,215) is directed to a pharmaceutical modified release (MR) methylphenidate dosage form, such as a capsule of methylphenidate indicated for the treatment of children with ADHD, capable of delivering a portion of the dose for rapid onset of action and the remainder of the dose in a controlled manner for about 12 hours. The dosage form is composed of a multitude of multicoated particles
3 made of two populations of drug layered beads, one population for immediate release and the other for extended release.
Canadian Patent Application No. 2,566,497 (Rubio Badia et al.) is directed to a multi-layered controlled release methylphenidate pellet, comprising an inert core, a first layer that contains methylphenidate and an acid buffering system, a protective layer, a layer of ethylcellulose (performs the function of controlling the extended release of most of the methylphenidate), and a second layer of methylphenidate, that is responsible for the immediate release of the aforesaid within one hour of administration.
International Patent Application WO 99/03471 discloses a methylphenidate preparation for extended release in which the innermost layer is coated in a layer of ammonium methacrylate polymer, and another layer that contains methylphenidate for immediate release resting on the ammonium methacrylate polymer layer.
Methylphenidate HCl formulations of the prior art require complicated manufacturing processes, which in turn consume significant amounts of time and are cost intensive.
There is thus a need for an invention, as described hereafter, that overcomes the problems of the prior art.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an extended release therapeutic drug delivery system comprising a core matrix composition. The core matrix composition comprises an active pharmaceutical ingredient and a release controlling agent. The drug delivery system further comprises a controlled release coating composition layer covering the core matrix composition.
Preferably, the active pharmaceutical ingredient is a central nervous system stimulant. More preferably, the active pharmaceutical ingredient is
Canadian Patent Application No. 2,566,497 (Rubio Badia et al.) is directed to a multi-layered controlled release methylphenidate pellet, comprising an inert core, a first layer that contains methylphenidate and an acid buffering system, a protective layer, a layer of ethylcellulose (performs the function of controlling the extended release of most of the methylphenidate), and a second layer of methylphenidate, that is responsible for the immediate release of the aforesaid within one hour of administration.
International Patent Application WO 99/03471 discloses a methylphenidate preparation for extended release in which the innermost layer is coated in a layer of ammonium methacrylate polymer, and another layer that contains methylphenidate for immediate release resting on the ammonium methacrylate polymer layer.
Methylphenidate HCl formulations of the prior art require complicated manufacturing processes, which in turn consume significant amounts of time and are cost intensive.
There is thus a need for an invention, as described hereafter, that overcomes the problems of the prior art.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an extended release therapeutic drug delivery system comprising a core matrix composition. The core matrix composition comprises an active pharmaceutical ingredient and a release controlling agent. The drug delivery system further comprises a controlled release coating composition layer covering the core matrix composition.
Preferably, the active pharmaceutical ingredient is a central nervous system stimulant. More preferably, the active pharmaceutical ingredient is
4 methylphenidate or a pharmaceutically acceptable salt thereof. In a preferred embodiment of the present invention, the active pharmaceutical ingredient is methylphenidate HCI.
In further embodiments of the present invention, the extended release therapeutic drug delivery system further comprises at least one pharmaceutically acceptable excipient, including binders, stabilizing agents, suspending agents, diluents, coating agents, lubricants, rate controlling polymers, emulsifying agents, solubilizing agents, glidants, absorbents, and disintegrants.
In a preferred embodiment of the present invention, the controlled release coating composition layer comprises a controlled release polymer and at least one other pharmaceutically acceptable excipient. The controlled release polymer is preferably an acrylic polymer such as Eudragit , and more preferably, the Eudragit is Eudragit RL 30D.
Preferably, the controlled release polymer accounts for between about 5 to about 40 % w/w of the drug delivery system, and more preferably, the controlled release polymer accounts for between about 5 to about 25 % w/w of the drug delivery system.
Preferably, the release controlling agent used in the core matrix composition accounts for between about 5 to about 40% w/w of the drug delivery system.
More preferably, the release controlling excipient used in the matrix accounts for between about 5 to about 25% w/w of the drug delivery system.
In a preferred embodiment, the release controlling agent present in the core matrix composition is a hydrophilic polymer such as HPMC-K4M, HPMC-K 100M
CR and HPMC-K 15M CR.
In a preferred embodiment, the at least one other pharmaceutically acceptable excipient present in the controlled release coating composition includes anti-tacking agents, anti-caking, agents, glidants, diluents, lubricants, plasticizers, additives, and surface active agents.
In a further aspect of the present invention there is provided a solid oral dosage form containing the extended release therapeutic drug delivery system as described herein. Preferably, the solid oral dosage form is in the form of a capsule or tablet. More preferably, the solid oral dosage form is in the form of a tablet.
Preferably, the solid oral dosage form is for use in once daily administration or twice daily administration.
In another aspect of the present invention there is provided a process for manufacturing the extended release therapeutic drug delivery system wherein said process comprises:
= a first step of combining an active pharmaceutical ingredient and a release controlling agent to form a mixture;
= a second step of blending the mixture;
= a third step of compressing the mixture from the second step to form a controlled release core matrix (the core matrix composition); and = a fourth step of applying a controlled release coating on the controlled release core.
Preferably, in the process according to the invention, the active pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable salt thereof, the controlled release polymer is Eudragit RL 30D and the release controlling agent used in the matrix is HPMC-K4M, HPMC-K 100M CR or HPMC-K
15M CR.
In a preferred embodiment, the amount of release controlling agent and controlled release polymer used in the process, in steps 1 and 4, respectively, results in the release controlling agent present in the core matrix composition accounting for between about 5 to about 40% w/w of the drug delivery system and the controlled release polymer accounts for between about 5 to about 40 % w/w of the drug delivery system. More preferably, the amount of release controlling agent and controlled release polymer used is such that the release controlling agent present in the core matrix composition accounts for between about 5 to about 25% w/w of the drug delivery system and the controlled release polymer accounts for between about to 25 % w/ w of the drug delivery system.
Other embodiments and further scope of applicability of the present invention will become apparent from the detailed description and examples given hereinafter. It should be understood, however, that this detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art.
An advantage associated with the present invention is an extended release solid oral dosage form that allows for the manufacture of solid oral dosage forms for once daily or twice daily administration with a sustained effect, made by a simplified production which is cost effective. An advantage associated with the present invention is that it gives the formulator the desired flexibility to obtain required in vitro dissolution characteristics. Another advantage of the present invention is that the composition can be formulated to obtain similar dissolution profiles regardless of the dosage strength of the active pharmaceutical ingredient ("API"). In this connection, it is worth mentioning that conventionally made controlled release matrix formulations cannot achieve this desired result, as formulators using this conventional technology have to formulate particular dosage strengths to a desired dissolution profile. The formulation according to the present invention has surprisingly been found to overcome this drawback found in the preparation of prior art formulations.
DETAILED DESCRIPTION OF THE INVENTION
Before the present formulations and methods of use are disclosed and described, it is to be understood by a person skilled in the art that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the disclosure and the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes mixtures of active agents, reference to "a pharmaceutical carrier" includes combinations of two or more carriers, and the like.
"Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
The terms or expressions "active agent", "drug", "pharmacologically active agent", "pharmaceutically acceptable active agent", "pharmaceutically acceptable active substance" and "active pharmaceutical ingredient" are used interchangeably herein to refer to a chemical material or compound which, when administered to an organism (human or animal, generally human) induces a desired pharmacologic effect. In the context of the present invention, the terms or expressions refer to a compound that is capable of being delivered orally.
The term "methylphenidate", as used herein, includes all optical isomers, racemic mixtures and the like of the compound and all pharmaceutically acceptable salts, amides, prodrugs and analogs thereof. For example, the pharmaceutically active substance can be for example, methylphenidate hydrochloride.
Similarly, a "pharmaceutically acceptable salt" or a "pharmaceutically acceptable ester" of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable. A pharmaceutically acceptable salt of methylphenidate is, for example, methylphenidate hydrochloride.
By the terms "effective amount" or "pharmaceutically effective amount" of an agent as provided herein are meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent administered, and the like. Thus, it is not possible to specify an exact "effective amount".
However, an appropriate "effective" amount in any individual case may be determined by person skilled in the art using routine experimentation.
The term "excipient" refers to a generally pharmaceutically inactive or inert substance used as a diluent or vehicle for a drug. Different forms of drug administration may require a different excipient and a "pharmaceutically acceptable excipient" includes a "pharmaceutically acceptable carrier". For example, tablets, troches, pills, capsules, and the like, may contain excipients including binders, such as gum tragacanth, acacia, corn starch or gelatin; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; and/or a flavoring agent such as peppermint, oil, wintergreen or cherry flavoring.
By "pharmaceutically acceptable carrier" is meant a carrier comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
The term "carrier" is used generically herein to refer to any components present in the pharmaceutical formulations other than the active agent or agents, and thus includes diluents, binders, lubricants, disintegrants, fillers, and coloring agents.
As aforementioned, the present invention relates to an extended release therapeutic drug delivery system comprising a core matrix composition and a controlled release coating composition.
The Applicant has developed a novel controlled release composition (dosage form) containing a combination of hydrophilic polymers, such as hydroxypropylmethylcellulose (HPMC), as a release controlling agent (or excipient) present in the core matrix composition, and a release controlling coating (comprising a controlled release polymer, such as Eudragit RL 30D) coated onto the HPMC
containing matrix core. As aforesaid, the present invention is directed to a novel controlled release dosage form for methylphenidate hydrochloride which may be used in the treatment of certain ailments, such as ADD, and a process to prepare such dosage forms.
The core matrix composition of the present invention is made of several components, including a pharmaceutically acceptable active substance (such as a CNS stimulant, in particular, methylphenidate or a pharmaceutically acceptable salt thereof) and a release controlling agent.
For example, the core matrix composition of the present invention can be illustrated as follows:
# Description mg/tab % Function 1. Meth 1 henidate HCl 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 diluent/Binder 3. HPMC-K4M 90.0 15.0 release controlling polymer 4. Stearic acid 3.0 0.5 tablet lubricant
In further embodiments of the present invention, the extended release therapeutic drug delivery system further comprises at least one pharmaceutically acceptable excipient, including binders, stabilizing agents, suspending agents, diluents, coating agents, lubricants, rate controlling polymers, emulsifying agents, solubilizing agents, glidants, absorbents, and disintegrants.
In a preferred embodiment of the present invention, the controlled release coating composition layer comprises a controlled release polymer and at least one other pharmaceutically acceptable excipient. The controlled release polymer is preferably an acrylic polymer such as Eudragit , and more preferably, the Eudragit is Eudragit RL 30D.
Preferably, the controlled release polymer accounts for between about 5 to about 40 % w/w of the drug delivery system, and more preferably, the controlled release polymer accounts for between about 5 to about 25 % w/w of the drug delivery system.
Preferably, the release controlling agent used in the core matrix composition accounts for between about 5 to about 40% w/w of the drug delivery system.
More preferably, the release controlling excipient used in the matrix accounts for between about 5 to about 25% w/w of the drug delivery system.
In a preferred embodiment, the release controlling agent present in the core matrix composition is a hydrophilic polymer such as HPMC-K4M, HPMC-K 100M
CR and HPMC-K 15M CR.
In a preferred embodiment, the at least one other pharmaceutically acceptable excipient present in the controlled release coating composition includes anti-tacking agents, anti-caking, agents, glidants, diluents, lubricants, plasticizers, additives, and surface active agents.
In a further aspect of the present invention there is provided a solid oral dosage form containing the extended release therapeutic drug delivery system as described herein. Preferably, the solid oral dosage form is in the form of a capsule or tablet. More preferably, the solid oral dosage form is in the form of a tablet.
Preferably, the solid oral dosage form is for use in once daily administration or twice daily administration.
In another aspect of the present invention there is provided a process for manufacturing the extended release therapeutic drug delivery system wherein said process comprises:
= a first step of combining an active pharmaceutical ingredient and a release controlling agent to form a mixture;
= a second step of blending the mixture;
= a third step of compressing the mixture from the second step to form a controlled release core matrix (the core matrix composition); and = a fourth step of applying a controlled release coating on the controlled release core.
Preferably, in the process according to the invention, the active pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable salt thereof, the controlled release polymer is Eudragit RL 30D and the release controlling agent used in the matrix is HPMC-K4M, HPMC-K 100M CR or HPMC-K
15M CR.
In a preferred embodiment, the amount of release controlling agent and controlled release polymer used in the process, in steps 1 and 4, respectively, results in the release controlling agent present in the core matrix composition accounting for between about 5 to about 40% w/w of the drug delivery system and the controlled release polymer accounts for between about 5 to about 40 % w/w of the drug delivery system. More preferably, the amount of release controlling agent and controlled release polymer used is such that the release controlling agent present in the core matrix composition accounts for between about 5 to about 25% w/w of the drug delivery system and the controlled release polymer accounts for between about to 25 % w/ w of the drug delivery system.
Other embodiments and further scope of applicability of the present invention will become apparent from the detailed description and examples given hereinafter. It should be understood, however, that this detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art.
An advantage associated with the present invention is an extended release solid oral dosage form that allows for the manufacture of solid oral dosage forms for once daily or twice daily administration with a sustained effect, made by a simplified production which is cost effective. An advantage associated with the present invention is that it gives the formulator the desired flexibility to obtain required in vitro dissolution characteristics. Another advantage of the present invention is that the composition can be formulated to obtain similar dissolution profiles regardless of the dosage strength of the active pharmaceutical ingredient ("API"). In this connection, it is worth mentioning that conventionally made controlled release matrix formulations cannot achieve this desired result, as formulators using this conventional technology have to formulate particular dosage strengths to a desired dissolution profile. The formulation according to the present invention has surprisingly been found to overcome this drawback found in the preparation of prior art formulations.
DETAILED DESCRIPTION OF THE INVENTION
Before the present formulations and methods of use are disclosed and described, it is to be understood by a person skilled in the art that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the disclosure and the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes mixtures of active agents, reference to "a pharmaceutical carrier" includes combinations of two or more carriers, and the like.
"Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
The terms or expressions "active agent", "drug", "pharmacologically active agent", "pharmaceutically acceptable active agent", "pharmaceutically acceptable active substance" and "active pharmaceutical ingredient" are used interchangeably herein to refer to a chemical material or compound which, when administered to an organism (human or animal, generally human) induces a desired pharmacologic effect. In the context of the present invention, the terms or expressions refer to a compound that is capable of being delivered orally.
The term "methylphenidate", as used herein, includes all optical isomers, racemic mixtures and the like of the compound and all pharmaceutically acceptable salts, amides, prodrugs and analogs thereof. For example, the pharmaceutically active substance can be for example, methylphenidate hydrochloride.
Similarly, a "pharmaceutically acceptable salt" or a "pharmaceutically acceptable ester" of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable. A pharmaceutically acceptable salt of methylphenidate is, for example, methylphenidate hydrochloride.
By the terms "effective amount" or "pharmaceutically effective amount" of an agent as provided herein are meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent administered, and the like. Thus, it is not possible to specify an exact "effective amount".
However, an appropriate "effective" amount in any individual case may be determined by person skilled in the art using routine experimentation.
The term "excipient" refers to a generally pharmaceutically inactive or inert substance used as a diluent or vehicle for a drug. Different forms of drug administration may require a different excipient and a "pharmaceutically acceptable excipient" includes a "pharmaceutically acceptable carrier". For example, tablets, troches, pills, capsules, and the like, may contain excipients including binders, such as gum tragacanth, acacia, corn starch or gelatin; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; and/or a flavoring agent such as peppermint, oil, wintergreen or cherry flavoring.
By "pharmaceutically acceptable carrier" is meant a carrier comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
The term "carrier" is used generically herein to refer to any components present in the pharmaceutical formulations other than the active agent or agents, and thus includes diluents, binders, lubricants, disintegrants, fillers, and coloring agents.
As aforementioned, the present invention relates to an extended release therapeutic drug delivery system comprising a core matrix composition and a controlled release coating composition.
The Applicant has developed a novel controlled release composition (dosage form) containing a combination of hydrophilic polymers, such as hydroxypropylmethylcellulose (HPMC), as a release controlling agent (or excipient) present in the core matrix composition, and a release controlling coating (comprising a controlled release polymer, such as Eudragit RL 30D) coated onto the HPMC
containing matrix core. As aforesaid, the present invention is directed to a novel controlled release dosage form for methylphenidate hydrochloride which may be used in the treatment of certain ailments, such as ADD, and a process to prepare such dosage forms.
The core matrix composition of the present invention is made of several components, including a pharmaceutically acceptable active substance (such as a CNS stimulant, in particular, methylphenidate or a pharmaceutically acceptable salt thereof) and a release controlling agent.
For example, the core matrix composition of the present invention can be illustrated as follows:
# Description mg/tab % Function 1. Meth 1 henidate HCl 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 diluent/Binder 3. HPMC-K4M 90.0 15.0 release controlling polymer 4. Stearic acid 3.0 0.5 tablet lubricant
5. Colloidal Silicon dioxide 6.0 1.0 glidant Total 600 100 -The controlled release coating composition of the present invention is made of a plurality of components. In the preferred embodiment, the controlled release coating composition contains a rate controlling polymer (i.e. a controlled release polymer, such as Eudragit) and at least one other pharmaceutically acceptable excipient. The one other pharmaceutically acceptable excipient includes anti-tacking agents, anti-caking agents, rate controlling polymers, glidants, diluents, lubricants, plasticizers, additives, and solvents.
The controlled release coating composition of the present invention can be illustrated as follows:
# Description mg/tab Function 1. Eudragit RL 30D 72.0 controlled release polymer 2. Talc 33.0 anti-tacking agent 3. Triethyl citrate 15.0 plasticizer 4. Purified water g.s. solvent Total 120 -Preferably, the polymer used in the core matrix composition should account for between 5 and 25 % by weight of the dosage form. Also preferably, the polymer used in the controlled release coating composition of the tablet should account for between 5 and 25 % by weight of the dosage form.
In a preferred embodiment, the polymer used in the core matrix composition is HPMC-K4M and the polymer used in the controlled release coating composition of the tablet is Eudragit RL 30D.
Active pharmaceutical ingredient The pharmaceutically acceptable active agents contemplated by the present invention include CNS stimulants, including analeptic agents and psychostimulants.
In particular, the preferred CNS stimulants include, but are not limited to, the following: amphetamine (racemic), d-amphetamine, amphetamine and d-amphetamine phosphate, amphetamine and d-amphetamine sulfate, amphetamine and d-amphetamine hydrochloride, amphetamine and d-amphetamine saccharate, and amphetamine and d-amphetamine aspartate, amphetaminil, bemegride, benzphetamine, benzphetamine hydrochloride, brucine, chlorphentermine, clofenciclan, clortermine, deanol acetamidobenzoate, demanyl phosphate, dexoxadrol, diethpropion, doxapram hydrochloride, N-ethylamphetamine, ethamivan, etifelmin, etryptamine, fencamfamine, fenethylline, fenosolone, fenfluramine, flurothyl, hexacyclonate sodium, homocamfin, mazindol, megexamide, methamphetamine, methylphenidate, methylphenidate hydrochloride, nicotinic agonists, nikethamide, pemoline, pentylenetetrazole, phenidimetrazine, phendimetrazine tartrate, phenmetrazine, phenmetrazine hydrochloride, phentermine, picrotoxin, pipradrol, pipradrol hydrochloride, prolintane, pyrovalerone, racephedrine, racephedrine hydrochloride, and tetrahydrobenzothienopyridines. The preferred pharmaceutically acceptable active agent of the present invention is methylphenidate and pharmaceutically acceptable salts thereof.
The pharmaceutically acceptable active agent or substance of the present invention could also be co-administered with another active agent or agents, for example, being co-administered with antidepressant agents, anti-anxiety agents, or other agents known to a person skilled in the art.
Each of the active agents in the individual tablets may be in the form of a pharmaceutically acceptable salt, ester, amide, prodrug or other derivative or analog, including active agents modified by appending one or more appropriate functionalities to enhance selected biological properties. Such modifications are considered to be part of the common general knowledge of a person skilled in the art.
Salts of the active agents used in conjunction with the present dosage forms may be obtained commercially or can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). Suitable acids for preparing acid addition salts may be weak acids, medium acids, or strong acids, and include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, aspartic acid, saccharic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Preparation of basic salts of acid moieties which may be present (e.g., carboxylic acid groups) are prepared using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, trimethylamine, or the like. Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups which may be present. These esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties which are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower alkyl. Pharmaceutically acceptable esters may be prepared using methods known to those skilled in the art and/or described in the pertinent literature.
Amides, prodrugs, and other analogs and derivatives can be readily prepared as well, using conventional means.
As aforesaid, the core matrix composition and controlled release coating composition can contain, in addition to the pharmaceutically acceptable active agents or substances active, several other components such as: diluents, binders, rate or release controlling polymers, lubricants, glidants, controlled release polymers, anti-tacking agents, plasticizers, solvents, and the like.
Diluents, also termed "fillers" are typically necessary to increase the bulk of a tablet so that a practical size is provided for compression. Suitable diluents include, for example, dicalcium phosphate dihydrate, dicalcium sulfate, calcium sulfate, sorbitol, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, hydrolyzed starches, starch, pregelatinized starch, silicon dioxide, titanium oxide, alumina, talc, microcrystalline cellulose, and powdered sugar.
Binders are used to impart cohesive qualities to a tablet formulation, and thus ensure that a tablet remains intact after compression. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., acacia, tragacanth, sodium alginate), polyvinylpyrrolidone, celluloses, "Veegum" , synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethyl cellulose, HPMC, methylcellulose, polyethylene oxide, and the like.
Suitable rate or release controlling polymers include cellulosic polymers such as HPMC, methacrylic acid copolymer, methacrylic acid copolymer dispersion, ethylcellulose, xanthun gum, polyethylene oxide, methylcellulose, and the like. Of course, other hydrophilic polymers can be used, including hydrophilic controlled release polymers (see hereinbelow).
Lubricants are used to facilitate tablet manufacture. Suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol, talc, stearic acid (chemically designated as octadecanoic acid, C18H3602), zinc stearate, sodium stearyl fumerate, calcium stearate. The lubricants are preferably present at no more than approximately 2 %
by weight of the tablet.
Suitable glidants include colloidal silicon dioxide, silicon dioxide (Si02), magnesium silicate, starch, talc, and magnesium trisilicate. Colloidal silicon dioxides are also known to function as an absorbent, anti-caking agent, emulsion stabilizer, glidant, suspending agent, tablet disintegrant, thermal stabilizer, and viscosity-increasing agent.
Controlled release polymers include HPMC K100M CR, HPMC K15M CR, ethylcellulose, Eudragit RL 30D, Eudragit RS 30D and combinations of these polymers. In this connection, Eudragit RL 30D (Rohm GmbH), Eudragit NE 30D
(Rohm GmbH), designated as poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2, can function as a film-former, tablet binder or tablet diluent. Eudragit RL is used to form water-insoluble film coats for sustained release products. Eudragit RL films are more permeable than those of Eudragit RS, and films of varying permeability can be obtained by mixing the two types together.
Anti-tacking agents include talc, colloidal silicon dioxide, magnesium stearate and PlasacrylTM.
Plasticizing agents include triethyl citrate and the related esters acetyltriethyl citrate, tributyl citrate, and acetyltributyl, which are known to be used to plasticize polymers in formulated pharmaceutical coatings. Triethyl citrate is also known to be used as a direct food additive for flavouring, for solvency and as a surface active agent.
Water or purified water, is used as a vehicle and/or solvent for the manufacture of drug products and pharmaceutical preparations. However, organic solvents may also be used for coating.
The novel drug dosage forms of the present invention are intended for oral administration for use in a mammal. In accordance with the present invention, administration of methylphenidate may be carried out in order to treat any disorder, condition or disease for which methylphenidate is generally indicated. Such disorders, conditions and diseases include, for example, ADD, ADHD, narcolepsy, and acute depression. Methylphenidate may also be used in the treatment of individuals suffering from cognitive decline associated with AIDS or AIDS-related conditions, and for mood elevation in terminally ill patients suffering from a disease such as cancer.
For administration of methylphenidate HC1, the typical daily dose is in the range of approximately 5 mg to 100 mg, and preferably in the range of approximately 5 mg to 60 mg. The exact dosage regimen will depend on a number of factors, including age, the general condition of the patient, the particular condition or disorder being treated, the severity of the patient's condition or disorder, and the like.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to persons skilled in the art to which the invention pertains.
EXAMPLES
The following examples are illustrative of the applicability of the present invention and are not intended to limit its scope. Modifications and variations can be made therein without depending from the spirit and scope of the invention.
Although any method and material whether similar or equivalent to those described herein can be used in the practice for testing the present invention, the preferred methods and materials as described.
All of the percentages given hereinabove and below are percentages by weight.
Example #1: Methylphenidate HCl Extended Release (XR) 54mg Tablets According to the Present Invention TABLE I - Core Matrix Co position # Description m tab % Function 1. Meth 1 henidate HCl 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 diluent/binder 3. HPMC-K4M 90.0 15.0 release controlling polymer 4. Stearic acid 3.0 0.5 tablet lubricant 5. Colloidal Silicon dioxide 6.0 1.0 glidant Total 600 100 -TABLE II - Controlled Release Coating Composition # Description mg/tab Function 1. Eudragit RL 72.0 controlled release polymer 2. Talc 33.0 anti-tacking agent 3. Triethyl citrate 15.0 plasticizer 4. Water q.s.* solvent Total 120 -*q.s. = quantity sufficient. Lost during the coating process.
Manufacturing Process In the first step (step #1), methylphenidate HCl (the API), lactose monohydrate, HPMC-K4M (the release controlling excipient) are mixed together in a suitable blender. In the second step (step #2), stearic acid and colloidal silicon dioxide were dispersed together in a poly bag and then passed through 40 mesh manual screen. After passing these products through the screen they were mixed with the contents of step #1 in a suitable blender. Afterwards, in step #3, the final blend, containing the elements of steps #1 and #2, was compressed using a rotary press, so as to form tablets.
The tablets manufactured in step #3 can then be coated with, for example a functional coat, containing the composition described in Table II. The coating process can be performed with conventional coating equipment, for example O'HARA Lab CoatTM equipped with a 15 inch pan.
In other words, the process for manufacturing a matrix controlled release drug delivery system according to the present invention generally comprises:
- a first step of combining a pharmaceutically acceptable active substance with at least one pharmaceutically acceptable excipient and mixing in a suitable blender;
- a second step of adding additional excipients and mixing in a suitable blender;
- a third step of compressing the blend formed from the first two steps into tablets; and - a fourth step of applying a controlled release coating composition on to the compressed tablets as a coating.
Example #2: Comparative Dissolution Between 18 and 54 mg Dosages of Methylphenidate TABLE III - Core Matrix Composition Description 54mg Stren h 18mg Stren h mg/tab %(w/w) mg/tab %(w/w) Meth 1 henidate HCl 54.0 9.0 18.0 4.0 Lactose monohydrate 447.0 74.5 357.75 79.50 HPMC-K 4M 90.0 15 67.50 15.0 Stearic acid 3.0 0.5 2.25 0.5 Colloidal silicon dioxide 6.0 1.0 4.50 1.0 Total 600 100 450 100 TABLE IV - Controlled Release Coating Composition Description 54mg strength 18 mg strength mg/tab mg/tab Eudragit RL 30D 72.0 54 Talc LM 33.0 24.75 Triethyl citrate 15.0 11.25 Purified water* g.s. g.s.
Total 120 90 *q.s. = quantity sufficient. Lost during the coating process.
Manufacturing Process In a first step (i.e. step #1), methylphenidate HCl (the API), lactose monohydrate, HPMC K4M (rate controlling polymer) are mixed together in a suitable blender. In a second step (i.e. step #2), stearic acid and colloidal silicon dioxide were dispersed together in a poly bag and then passed through 40 mesh manual screen. After passing these products through the screen they were mixed with the contents of step #1 in a suitable blender. Afterwards, in step #3, the final blend, containing the elements of steps #1 and #2, was compressed using a rotary press, so as to form tablets.
The tablets manufactured in step #3 can then be coated with a functional coat, such as the controlled release coating composition described in Table IV. The coating process can be performed with conventional coating equipment, for example a lab coat equipped with a 15 inch pan.
Direct compression of powder is a preferred manufacturing technique, though other dosage forms can be envisaged. For the purposes of the present invention, the tablet form is preferred.
TABLE V - Dissolution Data of testing in triplicate for both dosage forms Time (hrs) 18mg strength 54mg Strength Avg. % dissolution Avg. % dissolution 0.5 4 5 3.5 66 62 The dissolution parameters are listed as follows:
= USP Apparatus: II;
= paddle speed: 50rpm;
= media: 0.001N HCL; and = media volume: 900ml.
As it is evident from the dissolution data disclosed above in Table V, both the strengths exhibit similar dissolution profiles (f2 value = 74). Example 2 illustrates one of the advantages of the drug delivery system according to the present invention in achieving similar dissolution profiles for different strengths.
Example #3: Formulation Composition of Methylphenidate HCL XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at in Example #1.
Table VI - Core Matrix Composition Description 54mg Stren h mg/tab % w/w Meth 1 henidate HC1 54.0 10.80 Lactose monohydrate 338.50 77.7 HPMC-K 100M CR 50.0 10 Stearic acid 2.50 0.5 Colloidal silicon dioxide 5.0 1.0 Total 500 100 Table VII - Controlled Release Coating Composition Description m tab Eudragit RL 30D 30.0 Talc LM 13.75 Triethyl citrate 6.25 Purified water* g.s.
Total 50.0 *q.s. = quantity sufficient. Lost during the coating process.
Example #4: Dissolution of the Formulation Composition of Methylphenidate HC1 XR 54mg Tablets According to Example #3 The dissolution testing was done on the above mentioned formulation and the results are set out below in Table VIII.
Table VIII - Dissolution Profile Time (hrs) `Yo Dissolved 0.5 15 Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HCl and then change over to pH 6.8 phosphate buffer; and = media volume: 900m1.
Example #5: Formulation Composition of Methylphenidate HC1 XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at in Example #1.
TABLE IX - Core Matrix Composition Description 54mg Stren h mg/tab % w/w Meth 1 henidate HC1 54.0 10.80 Lactose monohydrate 338.50 77.7 HPMC-K 100M CR 50.0 10 Stearic acid 2.50 0.5 Colloidal silicon dioxide 5.0 1.0 Total 500 100 *q.s. = quantity sufficient. Lost during the coating process.
TABLE X - Controlled Release Coating Composition Description m tab Eudragit RL 30D 45.0 Talc LM 20.625 Triethylcitrate 9.375 Purified water* g.s.
Total 75.0 *q.s. = quantity sufficient. Lost during the coating process.
Example #6 - Dissolution of the Formulation Composition of Methylphenidate HC1 XR 54mg Tablets According to Example #5 The dissolution testing was done on the above mentioned formulation and the results are set out below in Table XI.
TABLE XI - Dissolution Profile Time (hrs) % Dissolved 0.5 11 Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HCl and then change over to pH 6.8 phosphate buffer; and = media volume: 900ml.
Example #7: Formulation Composition of Methylphenidate HC1 XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at in Example #1.
TABLE XII - Core Matrix Composition Description 54mg Stren h mg/tab % w/w Meth 1 henidate HCl 54.0 10.80 Lactose monohydrate 338.50 77.7 HPMC-K 15M CR 50.0 10 Stearic acid 2.50 0.5 Colloidal silicon dioxide 5.0 1.0 Total 500 100 TABLE XIII - Controlled Release Coating Composition Description mg/tab Eudragit RL 30D 30.0 Talc LM 13.75 Triethylcitrate 6.25 Purified water* g.s.
Total 50.0 *q.s. = quantity sufficient. Lost during the coating process.
Example #8: Dissolution of the Formulation Composition of Methylphenidate HC1 XR 54mg Tablets According to Example #7 The dissolution testing was done on the above mentioned development lot and the results are set out below in Table XIV.
TABLE XIV - Dissolution Profile Time (hrs) % Dissolved 0.5 19 Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HC1 and then change over to pH 6.8 phosphate buffer; and = media volume: 900m1.
The controlled release coating composition of the present invention can be illustrated as follows:
# Description mg/tab Function 1. Eudragit RL 30D 72.0 controlled release polymer 2. Talc 33.0 anti-tacking agent 3. Triethyl citrate 15.0 plasticizer 4. Purified water g.s. solvent Total 120 -Preferably, the polymer used in the core matrix composition should account for between 5 and 25 % by weight of the dosage form. Also preferably, the polymer used in the controlled release coating composition of the tablet should account for between 5 and 25 % by weight of the dosage form.
In a preferred embodiment, the polymer used in the core matrix composition is HPMC-K4M and the polymer used in the controlled release coating composition of the tablet is Eudragit RL 30D.
Active pharmaceutical ingredient The pharmaceutically acceptable active agents contemplated by the present invention include CNS stimulants, including analeptic agents and psychostimulants.
In particular, the preferred CNS stimulants include, but are not limited to, the following: amphetamine (racemic), d-amphetamine, amphetamine and d-amphetamine phosphate, amphetamine and d-amphetamine sulfate, amphetamine and d-amphetamine hydrochloride, amphetamine and d-amphetamine saccharate, and amphetamine and d-amphetamine aspartate, amphetaminil, bemegride, benzphetamine, benzphetamine hydrochloride, brucine, chlorphentermine, clofenciclan, clortermine, deanol acetamidobenzoate, demanyl phosphate, dexoxadrol, diethpropion, doxapram hydrochloride, N-ethylamphetamine, ethamivan, etifelmin, etryptamine, fencamfamine, fenethylline, fenosolone, fenfluramine, flurothyl, hexacyclonate sodium, homocamfin, mazindol, megexamide, methamphetamine, methylphenidate, methylphenidate hydrochloride, nicotinic agonists, nikethamide, pemoline, pentylenetetrazole, phenidimetrazine, phendimetrazine tartrate, phenmetrazine, phenmetrazine hydrochloride, phentermine, picrotoxin, pipradrol, pipradrol hydrochloride, prolintane, pyrovalerone, racephedrine, racephedrine hydrochloride, and tetrahydrobenzothienopyridines. The preferred pharmaceutically acceptable active agent of the present invention is methylphenidate and pharmaceutically acceptable salts thereof.
The pharmaceutically acceptable active agent or substance of the present invention could also be co-administered with another active agent or agents, for example, being co-administered with antidepressant agents, anti-anxiety agents, or other agents known to a person skilled in the art.
Each of the active agents in the individual tablets may be in the form of a pharmaceutically acceptable salt, ester, amide, prodrug or other derivative or analog, including active agents modified by appending one or more appropriate functionalities to enhance selected biological properties. Such modifications are considered to be part of the common general knowledge of a person skilled in the art.
Salts of the active agents used in conjunction with the present dosage forms may be obtained commercially or can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). Suitable acids for preparing acid addition salts may be weak acids, medium acids, or strong acids, and include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, aspartic acid, saccharic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Preparation of basic salts of acid moieties which may be present (e.g., carboxylic acid groups) are prepared using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, trimethylamine, or the like. Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups which may be present. These esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties which are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower alkyl. Pharmaceutically acceptable esters may be prepared using methods known to those skilled in the art and/or described in the pertinent literature.
Amides, prodrugs, and other analogs and derivatives can be readily prepared as well, using conventional means.
As aforesaid, the core matrix composition and controlled release coating composition can contain, in addition to the pharmaceutically acceptable active agents or substances active, several other components such as: diluents, binders, rate or release controlling polymers, lubricants, glidants, controlled release polymers, anti-tacking agents, plasticizers, solvents, and the like.
Diluents, also termed "fillers" are typically necessary to increase the bulk of a tablet so that a practical size is provided for compression. Suitable diluents include, for example, dicalcium phosphate dihydrate, dicalcium sulfate, calcium sulfate, sorbitol, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, hydrolyzed starches, starch, pregelatinized starch, silicon dioxide, titanium oxide, alumina, talc, microcrystalline cellulose, and powdered sugar.
Binders are used to impart cohesive qualities to a tablet formulation, and thus ensure that a tablet remains intact after compression. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., acacia, tragacanth, sodium alginate), polyvinylpyrrolidone, celluloses, "Veegum" , synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethyl cellulose, HPMC, methylcellulose, polyethylene oxide, and the like.
Suitable rate or release controlling polymers include cellulosic polymers such as HPMC, methacrylic acid copolymer, methacrylic acid copolymer dispersion, ethylcellulose, xanthun gum, polyethylene oxide, methylcellulose, and the like. Of course, other hydrophilic polymers can be used, including hydrophilic controlled release polymers (see hereinbelow).
Lubricants are used to facilitate tablet manufacture. Suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol, talc, stearic acid (chemically designated as octadecanoic acid, C18H3602), zinc stearate, sodium stearyl fumerate, calcium stearate. The lubricants are preferably present at no more than approximately 2 %
by weight of the tablet.
Suitable glidants include colloidal silicon dioxide, silicon dioxide (Si02), magnesium silicate, starch, talc, and magnesium trisilicate. Colloidal silicon dioxides are also known to function as an absorbent, anti-caking agent, emulsion stabilizer, glidant, suspending agent, tablet disintegrant, thermal stabilizer, and viscosity-increasing agent.
Controlled release polymers include HPMC K100M CR, HPMC K15M CR, ethylcellulose, Eudragit RL 30D, Eudragit RS 30D and combinations of these polymers. In this connection, Eudragit RL 30D (Rohm GmbH), Eudragit NE 30D
(Rohm GmbH), designated as poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2, can function as a film-former, tablet binder or tablet diluent. Eudragit RL is used to form water-insoluble film coats for sustained release products. Eudragit RL films are more permeable than those of Eudragit RS, and films of varying permeability can be obtained by mixing the two types together.
Anti-tacking agents include talc, colloidal silicon dioxide, magnesium stearate and PlasacrylTM.
Plasticizing agents include triethyl citrate and the related esters acetyltriethyl citrate, tributyl citrate, and acetyltributyl, which are known to be used to plasticize polymers in formulated pharmaceutical coatings. Triethyl citrate is also known to be used as a direct food additive for flavouring, for solvency and as a surface active agent.
Water or purified water, is used as a vehicle and/or solvent for the manufacture of drug products and pharmaceutical preparations. However, organic solvents may also be used for coating.
The novel drug dosage forms of the present invention are intended for oral administration for use in a mammal. In accordance with the present invention, administration of methylphenidate may be carried out in order to treat any disorder, condition or disease for which methylphenidate is generally indicated. Such disorders, conditions and diseases include, for example, ADD, ADHD, narcolepsy, and acute depression. Methylphenidate may also be used in the treatment of individuals suffering from cognitive decline associated with AIDS or AIDS-related conditions, and for mood elevation in terminally ill patients suffering from a disease such as cancer.
For administration of methylphenidate HC1, the typical daily dose is in the range of approximately 5 mg to 100 mg, and preferably in the range of approximately 5 mg to 60 mg. The exact dosage regimen will depend on a number of factors, including age, the general condition of the patient, the particular condition or disorder being treated, the severity of the patient's condition or disorder, and the like.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to persons skilled in the art to which the invention pertains.
EXAMPLES
The following examples are illustrative of the applicability of the present invention and are not intended to limit its scope. Modifications and variations can be made therein without depending from the spirit and scope of the invention.
Although any method and material whether similar or equivalent to those described herein can be used in the practice for testing the present invention, the preferred methods and materials as described.
All of the percentages given hereinabove and below are percentages by weight.
Example #1: Methylphenidate HCl Extended Release (XR) 54mg Tablets According to the Present Invention TABLE I - Core Matrix Co position # Description m tab % Function 1. Meth 1 henidate HCl 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 diluent/binder 3. HPMC-K4M 90.0 15.0 release controlling polymer 4. Stearic acid 3.0 0.5 tablet lubricant 5. Colloidal Silicon dioxide 6.0 1.0 glidant Total 600 100 -TABLE II - Controlled Release Coating Composition # Description mg/tab Function 1. Eudragit RL 72.0 controlled release polymer 2. Talc 33.0 anti-tacking agent 3. Triethyl citrate 15.0 plasticizer 4. Water q.s.* solvent Total 120 -*q.s. = quantity sufficient. Lost during the coating process.
Manufacturing Process In the first step (step #1), methylphenidate HCl (the API), lactose monohydrate, HPMC-K4M (the release controlling excipient) are mixed together in a suitable blender. In the second step (step #2), stearic acid and colloidal silicon dioxide were dispersed together in a poly bag and then passed through 40 mesh manual screen. After passing these products through the screen they were mixed with the contents of step #1 in a suitable blender. Afterwards, in step #3, the final blend, containing the elements of steps #1 and #2, was compressed using a rotary press, so as to form tablets.
The tablets manufactured in step #3 can then be coated with, for example a functional coat, containing the composition described in Table II. The coating process can be performed with conventional coating equipment, for example O'HARA Lab CoatTM equipped with a 15 inch pan.
In other words, the process for manufacturing a matrix controlled release drug delivery system according to the present invention generally comprises:
- a first step of combining a pharmaceutically acceptable active substance with at least one pharmaceutically acceptable excipient and mixing in a suitable blender;
- a second step of adding additional excipients and mixing in a suitable blender;
- a third step of compressing the blend formed from the first two steps into tablets; and - a fourth step of applying a controlled release coating composition on to the compressed tablets as a coating.
Example #2: Comparative Dissolution Between 18 and 54 mg Dosages of Methylphenidate TABLE III - Core Matrix Composition Description 54mg Stren h 18mg Stren h mg/tab %(w/w) mg/tab %(w/w) Meth 1 henidate HCl 54.0 9.0 18.0 4.0 Lactose monohydrate 447.0 74.5 357.75 79.50 HPMC-K 4M 90.0 15 67.50 15.0 Stearic acid 3.0 0.5 2.25 0.5 Colloidal silicon dioxide 6.0 1.0 4.50 1.0 Total 600 100 450 100 TABLE IV - Controlled Release Coating Composition Description 54mg strength 18 mg strength mg/tab mg/tab Eudragit RL 30D 72.0 54 Talc LM 33.0 24.75 Triethyl citrate 15.0 11.25 Purified water* g.s. g.s.
Total 120 90 *q.s. = quantity sufficient. Lost during the coating process.
Manufacturing Process In a first step (i.e. step #1), methylphenidate HCl (the API), lactose monohydrate, HPMC K4M (rate controlling polymer) are mixed together in a suitable blender. In a second step (i.e. step #2), stearic acid and colloidal silicon dioxide were dispersed together in a poly bag and then passed through 40 mesh manual screen. After passing these products through the screen they were mixed with the contents of step #1 in a suitable blender. Afterwards, in step #3, the final blend, containing the elements of steps #1 and #2, was compressed using a rotary press, so as to form tablets.
The tablets manufactured in step #3 can then be coated with a functional coat, such as the controlled release coating composition described in Table IV. The coating process can be performed with conventional coating equipment, for example a lab coat equipped with a 15 inch pan.
Direct compression of powder is a preferred manufacturing technique, though other dosage forms can be envisaged. For the purposes of the present invention, the tablet form is preferred.
TABLE V - Dissolution Data of testing in triplicate for both dosage forms Time (hrs) 18mg strength 54mg Strength Avg. % dissolution Avg. % dissolution 0.5 4 5 3.5 66 62 The dissolution parameters are listed as follows:
= USP Apparatus: II;
= paddle speed: 50rpm;
= media: 0.001N HCL; and = media volume: 900ml.
As it is evident from the dissolution data disclosed above in Table V, both the strengths exhibit similar dissolution profiles (f2 value = 74). Example 2 illustrates one of the advantages of the drug delivery system according to the present invention in achieving similar dissolution profiles for different strengths.
Example #3: Formulation Composition of Methylphenidate HCL XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at in Example #1.
Table VI - Core Matrix Composition Description 54mg Stren h mg/tab % w/w Meth 1 henidate HC1 54.0 10.80 Lactose monohydrate 338.50 77.7 HPMC-K 100M CR 50.0 10 Stearic acid 2.50 0.5 Colloidal silicon dioxide 5.0 1.0 Total 500 100 Table VII - Controlled Release Coating Composition Description m tab Eudragit RL 30D 30.0 Talc LM 13.75 Triethyl citrate 6.25 Purified water* g.s.
Total 50.0 *q.s. = quantity sufficient. Lost during the coating process.
Example #4: Dissolution of the Formulation Composition of Methylphenidate HC1 XR 54mg Tablets According to Example #3 The dissolution testing was done on the above mentioned formulation and the results are set out below in Table VIII.
Table VIII - Dissolution Profile Time (hrs) `Yo Dissolved 0.5 15 Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HCl and then change over to pH 6.8 phosphate buffer; and = media volume: 900m1.
Example #5: Formulation Composition of Methylphenidate HC1 XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at in Example #1.
TABLE IX - Core Matrix Composition Description 54mg Stren h mg/tab % w/w Meth 1 henidate HC1 54.0 10.80 Lactose monohydrate 338.50 77.7 HPMC-K 100M CR 50.0 10 Stearic acid 2.50 0.5 Colloidal silicon dioxide 5.0 1.0 Total 500 100 *q.s. = quantity sufficient. Lost during the coating process.
TABLE X - Controlled Release Coating Composition Description m tab Eudragit RL 30D 45.0 Talc LM 20.625 Triethylcitrate 9.375 Purified water* g.s.
Total 75.0 *q.s. = quantity sufficient. Lost during the coating process.
Example #6 - Dissolution of the Formulation Composition of Methylphenidate HC1 XR 54mg Tablets According to Example #5 The dissolution testing was done on the above mentioned formulation and the results are set out below in Table XI.
TABLE XI - Dissolution Profile Time (hrs) % Dissolved 0.5 11 Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HCl and then change over to pH 6.8 phosphate buffer; and = media volume: 900ml.
Example #7: Formulation Composition of Methylphenidate HC1 XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at in Example #1.
TABLE XII - Core Matrix Composition Description 54mg Stren h mg/tab % w/w Meth 1 henidate HCl 54.0 10.80 Lactose monohydrate 338.50 77.7 HPMC-K 15M CR 50.0 10 Stearic acid 2.50 0.5 Colloidal silicon dioxide 5.0 1.0 Total 500 100 TABLE XIII - Controlled Release Coating Composition Description mg/tab Eudragit RL 30D 30.0 Talc LM 13.75 Triethylcitrate 6.25 Purified water* g.s.
Total 50.0 *q.s. = quantity sufficient. Lost during the coating process.
Example #8: Dissolution of the Formulation Composition of Methylphenidate HC1 XR 54mg Tablets According to Example #7 The dissolution testing was done on the above mentioned development lot and the results are set out below in Table XIV.
TABLE XIV - Dissolution Profile Time (hrs) % Dissolved 0.5 19 Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HC1 and then change over to pH 6.8 phosphate buffer; and = media volume: 900m1.
Claims (27)
1. An extended release therapeutic drug delivery system comprising:
a core matrix composition;
said core matrix composition comprising an active pharmaceutical ingredient and a release controlling agent; and a controlled release coating composition layer covering the core matrix composition.
a core matrix composition;
said core matrix composition comprising an active pharmaceutical ingredient and a release controlling agent; and a controlled release coating composition layer covering the core matrix composition.
2. The extended release therapeutic drug delivery system according to claim 1, wherein the active pharmaceutical ingredient is a central nervous system stimulant.
3. The extended release therapeutic drug delivery system according to claim 2, wherein the active pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable salt thereof.
4. The extended release therapeutic drug delivery system according to claim 3, wherein the active pharmaceutical ingredient is methylphenidate hydrochloride.
5. The extended release therapeutic drug delivery system according to any one of claims 1 to 4, further comprising at least one pharmaceutically acceptable excipient, wherein said pharmaceutically acceptable excipient is a binder, diluent, coating agent, lubricant, rate controlling polymer, emulsifying agent, solubilizing agent, glidant, or absorbent.
6. The extended release therapeutic drug delivery system according to any one of claims 1 to 5, wherein the controlled release coating composition layer comprises a controlled release polymer and at least one other pharmaceutically acceptable excipient.
7. The extended release therapeutic drug delivery system according to claim 6, wherein the at least one other pharmaceutically acceptable excipient is an anti-tacking agent, anti-caking agent, glidant, diluent, lubricant, plasticizer, additive, surface active agent, or solvent.
8. The extended release therapeutic drug delivery system according to claims 6 or 7, wherein the controlled release polymer is an acrylic polymer.
9. The extended release therapeutic drug delivery system according to claim 8, wherein the acrylic polymer is Eudragit.
10. The extended release therapeutic drug delivery system according to claim 9, wherein the Eudragit is Eudragit RL 30D.
11. The extended release therapeutic drug delivery system according to any one of claims 6 to 10, wherein the controlled release polymer accounts for a total of about to about 40 % by weight of the drug delivery system.
12. The extended release therapeutic drug delivery system according to claim 11, wherein the controlled release polymer accounts for a total of about 5 to about 25 %
by weight of the drug delivery system.
by weight of the drug delivery system.
13. The extended release therapeutic drug delivery system according to any one of claims 1 to 11, wherein the release controlling agent in the core matrix composition accounts for a total of about 5 to about 40% by weight of the drug delivery system.
14. The extended release therapeutic drug delivery system according to claim 13, wherein the release controlling excipient used in the core matrix composition accounts for a total of about 5 to about 25 % by weight of the drug delivery system.
15. The extended release therapeutic drug delivery system according to any one of claims 1 to 14, wherein the release controlling agent in the core matrix composition is a hydrophilic polymer.
16. The extended release therapeutic drug delivery system according to claim 15, wherein the release controlling agent in the core matrix composition is HMPC-K4M, HPMC-K 100 M CR or HPMC-K 15 M CR.
17. A solid oral dosage form containing the extended release therapeutic drug delivery system according to any one of claims 1 to 16.
18. The solid oral dosage form according to claim 17, wherein the solid oral dosage form is in the form of a capsule or a tablet.
19. The solid oral dosage form according to claim 18, wherein the solid oral dosage form is in the form of a tablet.
20. The solid oral dosage form according to claims 18 or 19, wherein the active pharmaceutical ingredient is methylphenidate hydrochloride, and the methylphenidate hydrochloride is present in the dosage form in an amount of 18mg or 54 mg.
21. The solid oral dosage form according to any one of claims 17 to 20, wherein the solid oral dosage form is suitable for once daily administration.
22. The solid oral dosage form according to any one of claims 17 to 20, wherein the solid oral dosage form is suitable for twice daily administration.
23. A process for manufacturing the extended release therapeutic drug delivery system according to any one of claims 1 to 16, wherein said process comprises the following steps:
(i) a first step of combining an active pharmaceutical ingredient and a release controlling agent to form a mixture;
(ii) a second step of blending the mixture;
(iii) a third step of compressing the mixture from the second step to form a tablet; and (iv) a fourth step of applying a controlled release coating composition comprising a controlled release polymer onto the core matrix composition.
(i) a first step of combining an active pharmaceutical ingredient and a release controlling agent to form a mixture;
(ii) a second step of blending the mixture;
(iii) a third step of compressing the mixture from the second step to form a tablet; and (iv) a fourth step of applying a controlled release coating composition comprising a controlled release polymer onto the core matrix composition.
24. The process according to claim 23, wherein the active pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable salt thereof, the release controlling agent is HPMC-K4M, and the controlled release polymer is Eudragit.
25. The process according to claim 23 or 24, wherein the release controlling agent in the core matrix composition accounts for a total of about 5 to about 40 %
by weight of the drug delivery system and the controlled release polymer accounts for a total of about 5 to about 40 % by weight of the drug delivery system.
by weight of the drug delivery system and the controlled release polymer accounts for a total of about 5 to about 40 % by weight of the drug delivery system.
26. The process according to claim 25, wherein the release controlling agent in the core matrix composition accounts for a total of about 5 to about 25 % by weight of the drug delivery system and the controlled release polymer accounts for a total of about 5 to about 25 % by weight of the drug delivery system.
27. An extended release therapeutic drug delivery system comprising:
a core matrix composition;
said core matrix composition comprising methylphenidate or a pharmaceutically acceptable salt thereof, and a release controlling agent; and a controlled release coating composition layer covering the core matrix composition.
a core matrix composition;
said core matrix composition comprising methylphenidate or a pharmaceutically acceptable salt thereof, and a release controlling agent; and a controlled release coating composition layer covering the core matrix composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2718639A CA2718639C (en) | 2008-03-27 | 2009-03-26 | Methylphenidate extended release therapeutic drug delivery system |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2,627,198 | 2008-03-27 | ||
| CA002627198A CA2627198A1 (en) | 2008-03-27 | 2008-03-27 | Methylphenidate extended release therapeutic drug delivery system |
| CA2718639A CA2718639C (en) | 2008-03-27 | 2009-03-26 | Methylphenidate extended release therapeutic drug delivery system |
| PCT/CA2009/000369 WO2009117819A1 (en) | 2008-03-27 | 2009-03-26 | Methylphenidate extended release therapeutic drug delivery system |
Publications (2)
| Publication Number | Publication Date |
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| CA2718639A1 true CA2718639A1 (en) | 2009-10-01 |
| CA2718639C CA2718639C (en) | 2018-05-01 |
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| CA002627198A Abandoned CA2627198A1 (en) | 2008-03-27 | 2008-03-27 | Methylphenidate extended release therapeutic drug delivery system |
| CA2718639A Active CA2718639C (en) | 2008-03-27 | 2009-03-26 | Methylphenidate extended release therapeutic drug delivery system |
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| CA002627198A Abandoned CA2627198A1 (en) | 2008-03-27 | 2008-03-27 | Methylphenidate extended release therapeutic drug delivery system |
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| WO (1) | WO2009117819A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
| US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| US9028868B2 (en) | 2011-03-23 | 2015-05-12 | Ironshore Pharmaceuticals & Development, Inc. | Methods and compositions for treatment of attention deficit disorder |
| US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
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| US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
| US10292937B2 (en) | 2011-03-23 | 2019-05-21 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5837284A (en) * | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
| JP4613275B2 (en) * | 1998-11-02 | 2011-01-12 | エラン ファーマ インターナショナル，リミティド | Multiparticulate modified release composition |
| US6673367B1 (en) * | 1998-12-17 | 2004-01-06 | Euro-Celtique, S.A. | Controlled/modified release oral methylphenidate formulations |
| WO2003055475A1 (en) * | 2002-01-03 | 2003-07-10 | Lek Pharmaceutical And Chemical Company D.D. | Controlled release pharmaceutical formulation containing venlafaxine |
| CN1985810A (en) * | 2006-07-28 | 2007-06-27 | 中国人民解放军第二军医大学 | Slow control released methylphenidate hydrochloride capsule and its preparing method |
-
2008
- 2008-03-27 CA CA002627198A patent/CA2627198A1/en not_active Abandoned
-
2009
- 2009-03-26 WO PCT/CA2009/000369 patent/WO2009117819A1/en active Application Filing
- 2009-03-26 CA CA2718639A patent/CA2718639C/en active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2009117819A1 (en) | 2009-10-01 |
| CA2627198A1 (en) | 2009-09-27 |
| CA2718639C (en) | 2018-05-01 |
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