CA2627198A1 - Methylphenidate extended release therapeutic drug delivery system - Google Patents
Methylphenidate extended release therapeutic drug delivery system Download PDFInfo
- Publication number
- CA2627198A1 CA2627198A1 CA002627198A CA2627198A CA2627198A1 CA 2627198 A1 CA2627198 A1 CA 2627198A1 CA 002627198 A CA002627198 A CA 002627198A CA 2627198 A CA2627198 A CA 2627198A CA 2627198 A1 CA2627198 A1 CA 2627198A1
- Authority
- CA
- Canada
- Prior art keywords
- drug delivery
- delivery system
- therapeutic drug
- extended release
- release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 229940126585 therapeutic drug Drugs 0.000 title claims abstract description 27
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- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000003017 thermal stabilizer Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
Abstract
The present invention relates to an extended release therapeutic drug delivery system, comprising a controlled release core matrix comprising an active pharmaceutical ingredient; and a release controlling excipient; and a controlled release coating layer covering the core matrix composition, for use in once daily or twice daily administration and processes to manufacture such extended release therapeutic drug delivery system.
Description
METHYLPHENIDATE EXTENDED RELEASE
THERAPEUTIC DRUG DEL{VERY SYSTEM
FIELD OF THE 1NVENjION
The present invention relates to an extended release therapeutic drug delivery system, a process for the manufacturing the same, as well as the composition of the dosage fonn_ More speciflcally, the present invention relates to an extended release therapeutic system comprising methylphenidate as pharmaceutically acceptable active ingredient.
BAGKGROUND OF THE INVENTION
Methylphenidate (CAS [113-45-1]), 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, whereas niethylphenidate hydrochloride (CAS 1298-59-9]), a mild central nervous system (CNS) stimulant, C14H19NQz - HCI, is chemically designated as methyl a-phenyl-2-piperidineacetate hydrochloride. Its structural formula is H
N + HCI
Methylphenidate hydrochloride is known under various trade names, such as for example Ciba 4311,b; CentedrinO, ConcertaG, Equasym ; Metadate and RitalinO.
This compound is available in various forms of tablets of 5, 10, and 20 mg for oral administration, including for example RitalinO-SR, which is available as sustained-release tablets of 20 mg for oral administration.
Methylphenidate hydrochloride (HCI) is used in the treatment of Attention Deficit Disorder ("ADD"), a commonly diagnosed nervous system illness in children that is characterized by both distractability and impulsivity. Methylphenidate HCI is also used to treat a related disorder, Attention Deficit Hyperactivity Disorder ("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, and 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 inethylphenidate is described in, for example, L. Panizzon, Hehr. Chim_ Acta, 27, 1746 (1944), M. Hartmann, L. Panizzon in U.S_ patent no.
THERAPEUTIC DRUG DEL{VERY SYSTEM
FIELD OF THE 1NVENjION
The present invention relates to an extended release therapeutic drug delivery system, a process for the manufacturing the same, as well as the composition of the dosage fonn_ More speciflcally, the present invention relates to an extended release therapeutic system comprising methylphenidate as pharmaceutically acceptable active ingredient.
BAGKGROUND OF THE INVENTION
Methylphenidate (CAS [113-45-1]), 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, whereas niethylphenidate hydrochloride (CAS 1298-59-9]), a mild central nervous system (CNS) stimulant, C14H19NQz - HCI, is chemically designated as methyl a-phenyl-2-piperidineacetate hydrochloride. Its structural formula is H
N + HCI
Methylphenidate hydrochloride is known under various trade names, such as for example Ciba 4311,b; CentedrinO, ConcertaG, Equasym ; Metadate and RitalinO.
This compound is available in various forms of tablets of 5, 10, and 20 mg for oral administration, including for example RitalinO-SR, which is available as sustained-release tablets of 20 mg for oral administration.
Methylphenidate hydrochloride (HCI) is used in the treatment of Attention Deficit Disorder ("ADD"), a commonly diagnosed nervous system illness in children that is characterized by both distractability and impulsivity. Methylphenidate HCI is also used to treat a related disorder, Attention Deficit Hyperactivity Disorder ("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, and 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 inethylphenidate is described in, for example, L. Panizzon, Hehr. Chim_ Acta, 27, 1746 (1944), M. Hartmann, L. Panizzon in U.S_ patent no.
2,507,631 (1950 to Ciba).
Many formulations or dosage forms containing methylphenidate hydrochloride have been reported. For example, U.S. patent no. 6,344,215 B1 describes a methylphenidate composition in a gelatine capsule form, having two bead populations.
ConcertaOD is currently marketed as a tablet containing three layers in which is fotjnd methylphenidate. Concerta 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. This design allows the controlled release of drug in a unique and precise pattern. 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.
Canadian patent no. 2,264,852 (Gupta et al.) is directed to the use of a composition comprising 100 mg to 500 mg methylphenidate or a pharmaceutically acceptable salt thereof, together with a pharmaceuticalty 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.) is directed to a pharmaceutical modified release (MR) methylphenidate dosage form, such as a capsule of inethylphenidate indicated for the treatment of children with attention deficit hyperactivity disorder (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, is composed of a multitude of multicoated particles made of two populations of drug layered beads, IR (immediate release) and ER (extended release) beads.
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, that 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.
intemational 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, on which rests another layer that contains methylphenidate for immediate release.
Methylphenidate hydrochloride formulations of the prior art require complicated manufacturing processes, which in tum consume significant amounts of time and which 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 tNVENTION
An object of the present invention is to provide an extended release therapeutic drug delivery system, comprising a core matrix composition comprising: an active pharmaceutical ingredient; and a release controlling excipient; and a controlled release coating layer covering the core matrix composition.
Preferably, the active pharmaceutical ingredient is a central nervous system stimulant. More preferably, the active pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable salt thereof. Most preferably, the active pharmaceutical ingredient is methylphenidate hydrochloride.
Preferably, the extended release therapeutic drug delivery system further comprises at least one pharmaceutically acceptable excipient includes binding agents, binders, stabilizing agents, suspending agents, diluents, coating agents, lubricants, rate controlling polymers, emulsifying agents, solubifizing agents, glidants, absorbents, and disintegrants.
Also preferably, the controlled release coating layer comprises a controlled release polymer and at least one other pharmaceutically acceptable excipient.
More preferably, the controlled release polymer is an acrylic polymer such as Eudragit. Most preferably, the Eudragit is Eudragit RL 30D.
Preferably, the controlled release polymer accounts for between 5 to 40 % w!w of the composition. More preferably, the controiled release polymer accounts for between 5 to 25 % w/w of the composition. Preferably, the release controlling excipient used in the matrix accounts for between 5 to 40% w/w of the composition. More preferably, the release controlling excipient used in the matrix accounts for between 5 to 25%
w/w of the composition_ Preferably, the release controlling excipient used in the matrix is a cellulosic polymer such as HPMC-K4M, HPMC-K 100M CR and HPMC-K 15M CR.
Preferably, at least one other pharmaceutically acceptable excipient includes anti-tacking agents, anti-caking, agents, glidants, diluents, lubricants, piastioizers, additives, and surface active agents.
Another object of the present invention is to provide 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 fonn of a tablet. More preferably, the solid oral dosage form is in the form of a tablet_ Preferably, the soiid oral dosage form is for use in once daily administration or twice daily administration.
Another object of the present invention is to provide a process for manufacturing an extended release therapeutic drug deiivery system wherein said process comprises:
- a first step of combining an active pharmaceutical ingredient and a release controlling excipient 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;
- 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 methyiphenidate or a pharmaceutically acceptable salt thereof, the controlled release polymer is Eudragit RL 30D and the release controlling excipient used in the matrix is HPMC-K4M, HPMC-K 100M CR and HPMC-K 15M CR. Preferably also in the process according to the invention the release controlling excipient used in the matrix aCCounts for between 5 to 40% w/w of the composition and the controlled release pofymer accounts for between 5 to 40 % w!w of the corrtposition. More preferably also in the process according to the invention the release controlling excipient used in the matrix accounts for between 5 to 25% w/w of the composition and the controlled release polymer accounts for between 5 to 25 % w/w of the composition.
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 simiiar 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 can not achieve this desired result, as formulators using this conventional technoiogy 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 onry and is not intended to be limiting.
It must be noted that, as used in the specification and the appended 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.
"OptionaP" 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" and/or "pharmaceutically acceptable active substance" 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 "methyiphenidate" 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_ Preferably, according to the present invention, the pharmaceutically active substance can be for example, methylphenidate hydrochloride.
Similarly, a"phanr-aceutically acceptable salt' or a"phamlaceutically acceptable este' of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable. A pharmaceutically acceptable salt of inethylphenidate 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 pharmaceuticaliy 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 or wintergreen or cherry flavoring.
By "pharmaceutically acceptable carrier" is meant a canier 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 cnntained_ The term "can=ier" 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 composition and a controlled release coating composition.
More particularly, the Applicant has developed a novel controlled release composition (or dosage form) containing a combination of hydrophilic polymers such as HPMC as choice of release controlling agent in the core (or matrix), and release controlling coating (for example Eudragit RL 30D) on this said HPMC matrix. 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 attention deficit disorders and a process to make such dosage forms.
The core (or matrix) composition of the present invention is made of several components, such as for example a pharmaceutically acceptable active substance (i.e. a CNS stimulant, methyiphenidate or pharmaceutically acceptable salt thereof) combined with and at least one phanraceutically acceptable excipient.
For example, the core composition of the present invention can be illustrated as follows:
# Description M ltab % Function 1. Meth i henidate HCL 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 DiluentlBinder 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. For example, the controlled release coating composition can contain a rate controlling polymer (i.e. Eudragit) and at le-ast one other pharmaceutically acceptable excipient, such as, for example, anti-tacking agents, anti-caking, agents, controlled release polymers, glidants, diluents, lubricants, plasticizers, additives, and solvents.
For example, the controlled release coating composition of the present invention can be described as follows:
Descri tion 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 matrix should account for between 5 and 30 % wlw of the composition. Also preferably, the polymer used in the coating of the tablet should account for between 5 and 25 % w/w of the composition.
Preferably, the polymer to be used in the matrix is HPMC-K4M and the polymer to be used in the coating of the tablet is Eudragit RL 30D.
Active pharmaceutical ingredient Pharmaceutically acceptable active agents or active pharmaceutical ingredient ("API") contemplated by the present invention include CNS stimulants, including analeptic agents and paychostimulants. Particulariy preferred are CNS
stimulants including, but not limited to: amphetamine (racemic), d-amphetamine, amphetamine and d-amphetamine phosphate, amphetamine and d-amphetamine sulfate, amphetamine and d-amphetamine hydrochlaride, 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. Methylphenidate and salts thereof are particularly preferred pharmaceutically acceptable active agents according to the present invention.
It is worth mentioning that according to the present invention the pharmaceutically acceptable active agent or substance could be co-administered with another active agent, such as for example, antidepressant agents, antianxiety agents and 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 pharmaceuticaliy 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 modifcations are considered to be part of the common general knowledge of a person skilied 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, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed.
(New York: Wiley-Interscience, 1992). Suitable acids for preparing acid addition saits 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, maionic 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. saiicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, suifuric 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 functionaiization of hydroxyl andlor carboxyl groups which may be present. These esters are typically acyl-substituted derivatives of free aicohol 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 tablet 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.
Blnders 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, ceiluloses, and Veegum, and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcetlulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, polyethylene oxide, and the like.
Suitable rate or release controlling polymers Include cellulosic polymers such as hydroxylpropyl-methylcellulose (HPMC), methacrylic acid copolymer, msthacryiic 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; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol, talc, stearic acid (chemically designated as octadecanoic acid, C,BH36O2), zinc stearate, sodium stearyl fumerate, calcium stearate, and are preferably present at no more than approximately 2 wt.% relative to tablet weight.
Suitable glidants include colloidal silicon dioxide, silicon dioxide (Si02), magnesium silicate, starch, talc, magnesium trisilicate, etc. Colloidal silicion dioxides are also known to function as an absorbent; anti-caking agent: emulsion stabilizer; glidant;
suspending agent; tablet disintegrant; thermal stabilizer; viscosity-increasing agent.
Controlled release polymers Include HPMC K140M CR, HPMG K15M CR, Ethylcellulose, Eudragit RL 30D, Eudragit RS 30D and combination of both 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) 12- 0.2, has for function of being a film-former, tablet binder or tablet diluent.
Eudragit RL are 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 PlasacrylR_ 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 andlor solvent for the manufacture of drug products and pharmaceutical preparations. However, organic solvents may also be used for coating_ The novel drug dosage forms are intended for oral administration for use in a mammal and can be used to preferably administer methylphenidate to treat or prevent a variety of disorders, conditions and diseases. 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 hydrochloride, the typical daily dose is in the range of approximately 5 mg to 100 mg, preferably 5 mg to 60 mg. Although the exact dosage regimen will depend on a number of factors, including age, the general condition of the patient, the particular oondition 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.
Examoie # 1- Methvlnhenidate HCL extended release (XR) 54ma Tablets according to the present invention TABLEI
Core Tablet Composition Descri tion M ltab % Function 1. Meth l henidate HCL 54_0 9.0 API
2. Lactose rnonoh drate 447.0 74.5 Diluent/Binder 3. HPMC-K4M 90.0 15.0 Release controllin polymer 4. Stearlc acid 3.0 0.5 Tablet Iubrir,ant 5. Colloidal Siiicon dioxide 6.0 1.0 Glidant Total 600 100 -TABLE Ii Controlled Release Coating Composition # Description M ftab Function 1. Eudragit RL 30D 72.0 Controlled release polymer 2. Talc 33.0 Anti-tackin agent 3. Trieth I citrate 15.0 Plasticizer 4. Water g.s. Solvent Total 120 -It is worth mentioning that the purified water is lost during the coating process, and that the abbreviation "QS" refers to quantity sufficient.
Manufacturino Proeess:
In a first step (i.e. step #1), methylphenidate HCL, lactose monohydrate. HPMC-K4M 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.
It is worth mentioning that the tablets manufactured in step #3 could 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 Coat"m 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 and at least one pharmaceutically acceptable excipient so as to form a blend;
a second step of compressing said blend obtained in step 1: and a third step of applying a controlled release coating composition.
Example #2 - Comparative dissolution between 18 and 54 ma dosanes of Me hviahenidate TABLE ilI
Core matrix composition Description 54m Stre th 18mg Strength M /tab k w!w M /tab % w/w Meth I 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 87.50 15.0 Stearic acid 3.0 0.5 2.25 0.5 Colloidal silicon dioxide 6.0 1.0 4.50 1.0 TABLE IV
Controlled release coating composition Description Mg/tab Mg/tab 54mg strength 18 mg stren th Eudragit RL 30D 72.0 54 Talc LM 33.0 24.75 Tri Eth lcitrate 15.0 11.25 Purified water QS QS
Total 120 90 Lost during the coating process Manufacturing Process:
In a first step (i.e. step #1), methylphenidate HCL, lactose monohydrate, HPMC
K4M 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.
It is worth mentioning that the tablets manufactured in step #3 could be coated with, for example a functional coat, containing the 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. However, it is worth mentioning that other dosage forms can be envisaged; though for the purposes of the present invention, the tablet form is preferred.
TABLE V
Dissolution Data of testing in triplicate for both dosage fonrs Time (hrs) Average % dissolution Avei=age % dissolution 18mg strength 54mg Strength 0.5 4 5 3.5 66 62 The dissolution parameters are listed as follows:
- USP Apparatus: II;
- Paddle speed: 50rpm;
- Media: 0.001 N HCL; and Medial Volume: 900m1.
As it is evident from the dissolution data tabulated above (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 example #1.
Table VI
Core Matrix Composition Description 54m Stren h M ltab % w/w Meth I henidate HCL 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 Table VII
Controlled Release Coating Composition Description Mg/tab Eudragit RL 30D 30.0 Talc LM 13_75 Tri Ethylcitrate 6.25 Purified water QS
Total 50.0 ' Lost during the coating process Example #4: Dissolution of the Formulation Composition of Methylphenidate HCL
XR
54mg Tablets according to Example #3 The dissolution testing was done on the above mentioned formulation and the results are tabulated below.
TABLE VIII
Dissolution Profile:
Time (hrs) % Dissolved 0.5 15 Dissolution Method:
Media - 0.5 and 1 hr in 0. 0D1 N HCL and then change over to pH-6.8 phosphate buffer.
Apparatus I (USP Paddles) with sinkers Speed- 50rpm Volume - 900m1 Exampt #5: Fomiuiation Composition of Methylphenidate HCL XR 54mg Tablets The tablets of this example were made in accordance with the manuPacturing process set out at example #1.
TABLE IX
Core Matrix Composition Description 54m Stren h M /tab k w/w Meth 1 henidate HCL 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 TABLE X
Controlled Release Coating Composition Description M tab Eudragit RL 30D 45.0 Talc LM 20.625 Tri Eth icitrate 9.375 Purified water QS
Total 75.0 Lost during the coating process Example #6: Dissolution of the Formulation Composition of Methylphenidate HCL
XR
54mg Tablets according to Example #5 The dissolution testing was done on the above mentioned formulation and the resuits are tabulated below.
TABLE Xi Dissolution Profile Time (hrs) % Dissoived 0.5 11 Dissolution Method:
Media - 0.5 and 1 hr in 0.001 N HCL and then Change over to pH-6.8 phosphate buffer.
Apparatus I(USP Paddles) with sinkers Speed- 50rpm Volume - 900m1 Example #7: Fomlulation Composition of Methylphenidate HCL XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at example #1.
TABLE XII
Core Matrix Composition Description 54m Stren th Mg/tab % w/w Meth I henidate HCL 54_0 10.80 Lactose monoh drate 338.50 77.7 HPMC-K 16M CR 50.0 10 Stearic acid 2.50 0.5 Colioidal silicon dioxide 5.0 1.0 Controlled Release Coating Composition TABLE XUI
Description M /tab Eudragit RL 30D 30.0 Talc LM 13.75 Tri Ethylcitrate 6.25 Purified water' QS
Total 50.0 ' Lost during the coating process Example #8: Dissolution of the Formulation Composition of Methylphenidate HCL
XR
54mg Tablets according to Example #7 The dissolution testing was done on the above mentioned development lot and the results are tabulated below.
TABLEXIV
Dissolution Profile:
Time hrs % Dissolved 0.5 19 Dissolution Method' Media - 0.5 and lhr in 0.001 N HCL and then change over to pH-6.8 phosphate buffer.
Apparatus I (USP Paddles) with sinkers Speed- 50rpm Volume - 900mi
Many formulations or dosage forms containing methylphenidate hydrochloride have been reported. For example, U.S. patent no. 6,344,215 B1 describes a methylphenidate composition in a gelatine capsule form, having two bead populations.
ConcertaOD is currently marketed as a tablet containing three layers in which is fotjnd methylphenidate. Concerta 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. This design allows the controlled release of drug in a unique and precise pattern. 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.
Canadian patent no. 2,264,852 (Gupta et al.) is directed to the use of a composition comprising 100 mg to 500 mg methylphenidate or a pharmaceutically acceptable salt thereof, together with a pharmaceuticalty 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.) is directed to a pharmaceutical modified release (MR) methylphenidate dosage form, such as a capsule of inethylphenidate indicated for the treatment of children with attention deficit hyperactivity disorder (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, is composed of a multitude of multicoated particles made of two populations of drug layered beads, IR (immediate release) and ER (extended release) beads.
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, that 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.
intemational 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, on which rests another layer that contains methylphenidate for immediate release.
Methylphenidate hydrochloride formulations of the prior art require complicated manufacturing processes, which in tum consume significant amounts of time and which 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 tNVENTION
An object of the present invention is to provide an extended release therapeutic drug delivery system, comprising a core matrix composition comprising: an active pharmaceutical ingredient; and a release controlling excipient; and a controlled release coating layer covering the core matrix composition.
Preferably, the active pharmaceutical ingredient is a central nervous system stimulant. More preferably, the active pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable salt thereof. Most preferably, the active pharmaceutical ingredient is methylphenidate hydrochloride.
Preferably, the extended release therapeutic drug delivery system further comprises at least one pharmaceutically acceptable excipient includes binding agents, binders, stabilizing agents, suspending agents, diluents, coating agents, lubricants, rate controlling polymers, emulsifying agents, solubifizing agents, glidants, absorbents, and disintegrants.
Also preferably, the controlled release coating layer comprises a controlled release polymer and at least one other pharmaceutically acceptable excipient.
More preferably, the controlled release polymer is an acrylic polymer such as Eudragit. Most preferably, the Eudragit is Eudragit RL 30D.
Preferably, the controlled release polymer accounts for between 5 to 40 % w!w of the composition. More preferably, the controiled release polymer accounts for between 5 to 25 % w/w of the composition. Preferably, the release controlling excipient used in the matrix accounts for between 5 to 40% w/w of the composition. More preferably, the release controlling excipient used in the matrix accounts for between 5 to 25%
w/w of the composition_ Preferably, the release controlling excipient used in the matrix is a cellulosic polymer such as HPMC-K4M, HPMC-K 100M CR and HPMC-K 15M CR.
Preferably, at least one other pharmaceutically acceptable excipient includes anti-tacking agents, anti-caking, agents, glidants, diluents, lubricants, piastioizers, additives, and surface active agents.
Another object of the present invention is to provide 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 fonn of a tablet. More preferably, the solid oral dosage form is in the form of a tablet_ Preferably, the soiid oral dosage form is for use in once daily administration or twice daily administration.
Another object of the present invention is to provide a process for manufacturing an extended release therapeutic drug deiivery system wherein said process comprises:
- a first step of combining an active pharmaceutical ingredient and a release controlling excipient 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;
- 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 methyiphenidate or a pharmaceutically acceptable salt thereof, the controlled release polymer is Eudragit RL 30D and the release controlling excipient used in the matrix is HPMC-K4M, HPMC-K 100M CR and HPMC-K 15M CR. Preferably also in the process according to the invention the release controlling excipient used in the matrix aCCounts for between 5 to 40% w/w of the composition and the controlled release pofymer accounts for between 5 to 40 % w!w of the corrtposition. More preferably also in the process according to the invention the release controlling excipient used in the matrix accounts for between 5 to 25% w/w of the composition and the controlled release polymer accounts for between 5 to 25 % w/w of the composition.
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 simiiar 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 can not achieve this desired result, as formulators using this conventional technoiogy 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 onry and is not intended to be limiting.
It must be noted that, as used in the specification and the appended 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.
"OptionaP" 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" and/or "pharmaceutically acceptable active substance" 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 "methyiphenidate" 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_ Preferably, according to the present invention, the pharmaceutically active substance can be for example, methylphenidate hydrochloride.
Similarly, a"phanr-aceutically acceptable salt' or a"phamlaceutically acceptable este' of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable. A pharmaceutically acceptable salt of inethylphenidate 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 pharmaceuticaliy 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 or wintergreen or cherry flavoring.
By "pharmaceutically acceptable carrier" is meant a canier 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 cnntained_ The term "can=ier" 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 composition and a controlled release coating composition.
More particularly, the Applicant has developed a novel controlled release composition (or dosage form) containing a combination of hydrophilic polymers such as HPMC as choice of release controlling agent in the core (or matrix), and release controlling coating (for example Eudragit RL 30D) on this said HPMC matrix. 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 attention deficit disorders and a process to make such dosage forms.
The core (or matrix) composition of the present invention is made of several components, such as for example a pharmaceutically acceptable active substance (i.e. a CNS stimulant, methyiphenidate or pharmaceutically acceptable salt thereof) combined with and at least one phanraceutically acceptable excipient.
For example, the core composition of the present invention can be illustrated as follows:
# Description M ltab % Function 1. Meth i henidate HCL 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 DiluentlBinder 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. For example, the controlled release coating composition can contain a rate controlling polymer (i.e. Eudragit) and at le-ast one other pharmaceutically acceptable excipient, such as, for example, anti-tacking agents, anti-caking, agents, controlled release polymers, glidants, diluents, lubricants, plasticizers, additives, and solvents.
For example, the controlled release coating composition of the present invention can be described as follows:
Descri tion 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 matrix should account for between 5 and 30 % wlw of the composition. Also preferably, the polymer used in the coating of the tablet should account for between 5 and 25 % w/w of the composition.
Preferably, the polymer to be used in the matrix is HPMC-K4M and the polymer to be used in the coating of the tablet is Eudragit RL 30D.
Active pharmaceutical ingredient Pharmaceutically acceptable active agents or active pharmaceutical ingredient ("API") contemplated by the present invention include CNS stimulants, including analeptic agents and paychostimulants. Particulariy preferred are CNS
stimulants including, but not limited to: amphetamine (racemic), d-amphetamine, amphetamine and d-amphetamine phosphate, amphetamine and d-amphetamine sulfate, amphetamine and d-amphetamine hydrochlaride, 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. Methylphenidate and salts thereof are particularly preferred pharmaceutically acceptable active agents according to the present invention.
It is worth mentioning that according to the present invention the pharmaceutically acceptable active agent or substance could be co-administered with another active agent, such as for example, antidepressant agents, antianxiety agents and 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 pharmaceuticaliy 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 modifcations are considered to be part of the common general knowledge of a person skilied 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, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed.
(New York: Wiley-Interscience, 1992). Suitable acids for preparing acid addition saits 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, maionic 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. saiicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, suifuric 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 functionaiization of hydroxyl andlor carboxyl groups which may be present. These esters are typically acyl-substituted derivatives of free aicohol 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 tablet 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.
Blnders 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, ceiluloses, and Veegum, and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcetlulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, polyethylene oxide, and the like.
Suitable rate or release controlling polymers Include cellulosic polymers such as hydroxylpropyl-methylcellulose (HPMC), methacrylic acid copolymer, msthacryiic 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; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol, talc, stearic acid (chemically designated as octadecanoic acid, C,BH36O2), zinc stearate, sodium stearyl fumerate, calcium stearate, and are preferably present at no more than approximately 2 wt.% relative to tablet weight.
Suitable glidants include colloidal silicon dioxide, silicon dioxide (Si02), magnesium silicate, starch, talc, magnesium trisilicate, etc. Colloidal silicion dioxides are also known to function as an absorbent; anti-caking agent: emulsion stabilizer; glidant;
suspending agent; tablet disintegrant; thermal stabilizer; viscosity-increasing agent.
Controlled release polymers Include HPMC K140M CR, HPMG K15M CR, Ethylcellulose, Eudragit RL 30D, Eudragit RS 30D and combination of both 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) 12- 0.2, has for function of being a film-former, tablet binder or tablet diluent.
Eudragit RL are 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 PlasacrylR_ 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 andlor solvent for the manufacture of drug products and pharmaceutical preparations. However, organic solvents may also be used for coating_ The novel drug dosage forms are intended for oral administration for use in a mammal and can be used to preferably administer methylphenidate to treat or prevent a variety of disorders, conditions and diseases. 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 hydrochloride, the typical daily dose is in the range of approximately 5 mg to 100 mg, preferably 5 mg to 60 mg. Although the exact dosage regimen will depend on a number of factors, including age, the general condition of the patient, the particular oondition 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.
Examoie # 1- Methvlnhenidate HCL extended release (XR) 54ma Tablets according to the present invention TABLEI
Core Tablet Composition Descri tion M ltab % Function 1. Meth l henidate HCL 54_0 9.0 API
2. Lactose rnonoh drate 447.0 74.5 Diluent/Binder 3. HPMC-K4M 90.0 15.0 Release controllin polymer 4. Stearlc acid 3.0 0.5 Tablet Iubrir,ant 5. Colloidal Siiicon dioxide 6.0 1.0 Glidant Total 600 100 -TABLE Ii Controlled Release Coating Composition # Description M ftab Function 1. Eudragit RL 30D 72.0 Controlled release polymer 2. Talc 33.0 Anti-tackin agent 3. Trieth I citrate 15.0 Plasticizer 4. Water g.s. Solvent Total 120 -It is worth mentioning that the purified water is lost during the coating process, and that the abbreviation "QS" refers to quantity sufficient.
Manufacturino Proeess:
In a first step (i.e. step #1), methylphenidate HCL, lactose monohydrate. HPMC-K4M 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.
It is worth mentioning that the tablets manufactured in step #3 could 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 Coat"m 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 and at least one pharmaceutically acceptable excipient so as to form a blend;
a second step of compressing said blend obtained in step 1: and a third step of applying a controlled release coating composition.
Example #2 - Comparative dissolution between 18 and 54 ma dosanes of Me hviahenidate TABLE ilI
Core matrix composition Description 54m Stre th 18mg Strength M /tab k w!w M /tab % w/w Meth I 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 87.50 15.0 Stearic acid 3.0 0.5 2.25 0.5 Colloidal silicon dioxide 6.0 1.0 4.50 1.0 TABLE IV
Controlled release coating composition Description Mg/tab Mg/tab 54mg strength 18 mg stren th Eudragit RL 30D 72.0 54 Talc LM 33.0 24.75 Tri Eth lcitrate 15.0 11.25 Purified water QS QS
Total 120 90 Lost during the coating process Manufacturing Process:
In a first step (i.e. step #1), methylphenidate HCL, lactose monohydrate, HPMC
K4M 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.
It is worth mentioning that the tablets manufactured in step #3 could be coated with, for example a functional coat, containing the 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. However, it is worth mentioning that other dosage forms can be envisaged; though for the purposes of the present invention, the tablet form is preferred.
TABLE V
Dissolution Data of testing in triplicate for both dosage fonrs Time (hrs) Average % dissolution Avei=age % dissolution 18mg strength 54mg Strength 0.5 4 5 3.5 66 62 The dissolution parameters are listed as follows:
- USP Apparatus: II;
- Paddle speed: 50rpm;
- Media: 0.001 N HCL; and Medial Volume: 900m1.
As it is evident from the dissolution data tabulated above (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 example #1.
Table VI
Core Matrix Composition Description 54m Stren h M ltab % w/w Meth I henidate HCL 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 Table VII
Controlled Release Coating Composition Description Mg/tab Eudragit RL 30D 30.0 Talc LM 13_75 Tri Ethylcitrate 6.25 Purified water QS
Total 50.0 ' Lost during the coating process Example #4: Dissolution of the Formulation Composition of Methylphenidate HCL
XR
54mg Tablets according to Example #3 The dissolution testing was done on the above mentioned formulation and the results are tabulated below.
TABLE VIII
Dissolution Profile:
Time (hrs) % Dissolved 0.5 15 Dissolution Method:
Media - 0.5 and 1 hr in 0. 0D1 N HCL and then change over to pH-6.8 phosphate buffer.
Apparatus I (USP Paddles) with sinkers Speed- 50rpm Volume - 900m1 Exampt #5: Fomiuiation Composition of Methylphenidate HCL XR 54mg Tablets The tablets of this example were made in accordance with the manuPacturing process set out at example #1.
TABLE IX
Core Matrix Composition Description 54m Stren h M /tab k w/w Meth 1 henidate HCL 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 TABLE X
Controlled Release Coating Composition Description M tab Eudragit RL 30D 45.0 Talc LM 20.625 Tri Eth icitrate 9.375 Purified water QS
Total 75.0 Lost during the coating process Example #6: Dissolution of the Formulation Composition of Methylphenidate HCL
XR
54mg Tablets according to Example #5 The dissolution testing was done on the above mentioned formulation and the resuits are tabulated below.
TABLE Xi Dissolution Profile Time (hrs) % Dissoived 0.5 11 Dissolution Method:
Media - 0.5 and 1 hr in 0.001 N HCL and then Change over to pH-6.8 phosphate buffer.
Apparatus I(USP Paddles) with sinkers Speed- 50rpm Volume - 900m1 Example #7: Fomlulation Composition of Methylphenidate HCL XR 54mg Tablets The tablets of this example were made in accordance with the manufacturing process set out at example #1.
TABLE XII
Core Matrix Composition Description 54m Stren th Mg/tab % w/w Meth I henidate HCL 54_0 10.80 Lactose monoh drate 338.50 77.7 HPMC-K 16M CR 50.0 10 Stearic acid 2.50 0.5 Colioidal silicon dioxide 5.0 1.0 Controlled Release Coating Composition TABLE XUI
Description M /tab Eudragit RL 30D 30.0 Talc LM 13.75 Tri Ethylcitrate 6.25 Purified water' QS
Total 50.0 ' Lost during the coating process Example #8: Dissolution of the Formulation Composition of Methylphenidate HCL
XR
54mg Tablets according to Example #7 The dissolution testing was done on the above mentioned development lot and the results are tabulated below.
TABLEXIV
Dissolution Profile:
Time hrs % Dissolved 0.5 19 Dissolution Method' Media - 0.5 and lhr in 0.001 N HCL and then change over to pH-6.8 phosphate buffer.
Apparatus I (USP Paddles) with sinkers Speed- 50rpm Volume - 900mi
Claims (24)
1. An extended release therapeutic drug delivery system, comprising - a controlled release core matrix comprising - an active pharmaceutical ingredient; and - a release controlling excipient; and - a controlled release coating 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 2 or 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 includes binding agents, binders, diluents, coating agents, lubricants, rate controlling polymers, emulsifying agents, solubilizing agents, glidants, and absorbents.
6. The extended release therapeutic drug delivery system according to any one of claims 1 to 5, wherein the controlled release coating 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 controlled release polymer is an acrylic polymer.
8. The extended release therapeutic drug delivery system according to claim 7, wherein the acrylic polymer is Eudragit.
9. The extended release therapeutic drug delivery system according to claim 8, wherein the Eudragit is Eudragit RL 30D.
10. The extended release therapeutic drug delivery system according to claim 9, wherein the controlled release polymer accounts for between 5 to 40 % w/w of the composition.
11. The extended release therapeutic drug delivery system according to claim 9, wherein the controlled release polymer accounts for between 5 to 25 % w/w of the composition.
12. The extended release therapeutic drug delivery system according to any one of claims 1 to 10, wherein the release controlling excipient used in the matrix accounts for between 5 to 40% w/w of the composition.
13. The extended release therapeutic drug delivery system according to any one of claims 1 to 10, wherein the release controlling excipient used in the matrix accounts for between 5 to 25% w/w of the composition.
14. The extended release therapeutic drug delivery system according to any one of claims 1 to 13, wherein the release controlling excipient used in the matrix is a hydrophilic polymer such as HPMC-K4M, HPMC-K 100M CR and HPMC-K 15M CR.
15. The extended release therapeutic drug delivery system according to claim 6, wherein the at least one other pharmaceutically acceptable excipient includes anti-tacking agents, anti-caking, agents, glidants, diluents, lubricants, plasticizers, additives, surface active agents, and solvents.
16. A solid oral dosage form containing the extended release therapeutic drug delivery system according to any one of claims 1 to 15.
17. The solid oral dosage form according to claim 16 is in the form of a capsule or a tablet.
18. The solid oral dosage form according to claim 17 is in the form of a tablet.
19 The solid oral dosage form according to any one of claims 16 to 18 for once daily administration.
20. The solid oral dosage form according to any one of claims 16 to 18 for twice daily administration.
21. A process for manufacturing an extended release therapeutic drug delivery system according to any one of claims 1 to 15, wherein said process comprises:
- a first step of combining an active pharmaceutical ingredient and a release controlling excipient 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;
- a fourth step of applying a controlled release coating on the controlled release core.
- a first step of combining an active pharmaceutical ingredient and a release controlling excipient 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;
- a fourth step of applying a controlled release coating on the controlled release core.
22. Process according to claim 21, wherein the active pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable salt thereof, the controlled release polymer is Eudragit and the release controlling excipient used in the matrix is HPMC-K4M.
23. Process according to claim 21 or 22, wherein the release controlling excipient used in the matrix accounts for between 5 to 40% w/w of the composition and the controlled release polymer accounts for between 5 to 40 % w/w of the composition.
24. Process according to claim 23, wherein the release controlling excipient used in the matrix accounts for between 5 to 25% w/w of the composition and the controlled release polymer accounts for between 5 to 25 % w/w of the composition.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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CA002627198A CA2627198A1 (en) | 2008-03-27 | 2008-03-27 | 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 |
CA2718639A CA2718639C (en) | 2008-03-27 | 2009-03-26 | Methylphenidate extended release therapeutic drug delivery system |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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CA002627198A CA2627198A1 (en) | 2008-03-27 | 2008-03-27 | Methylphenidate extended release therapeutic drug delivery system |
Publications (1)
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CA2627198A1 true CA2627198A1 (en) | 2009-09-27 |
Family
ID=41112885
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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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CA2718639A Active CA2718639C (en) | 2008-03-27 | 2009-03-26 | Methylphenidate extended release therapeutic drug delivery system |
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WO (1) | WO2009117819A1 (en) |
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US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of 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 |
US9283214B2 (en) | 2011-03-23 | 2016-03-15 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for 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 |
US10905652B2 (en) | 2011-03-23 | 2021-02-02 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
WO2012129551A1 (en) | 2011-03-23 | 2012-09-27 | Ironshore Pharmaceuticals & Development, Inc. | Methods and compositions for treatment of attention deficit disorder |
US11241391B2 (en) | 2011-03-23 | 2022-02-08 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
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US5837284A (en) * | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
DK1126826T6 (en) * | 1998-11-02 | 2019-06-24 | Alkermes Pharma Ireland Ltd | Multiparticulate modified release of methylphenidate |
US6673367B1 (en) * | 1998-12-17 | 2004-01-06 | Euro-Celtique, S.A. | Controlled/modified release oral methylphenidate formulations |
AU2002217373A1 (en) * | 2002-01-03 | 2003-07-15 | 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
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2009
- 2009-03-26 WO PCT/CA2009/000369 patent/WO2009117819A1/en active Application Filing
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CA2718639C (en) | 2018-05-01 |
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