WO2015150948A1 - Modified release solid oral pharmaceutical compositions of cyclobenzaprine or a salt thereof - Google Patents

Modified release solid oral pharmaceutical compositions of cyclobenzaprine or a salt thereof Download PDF

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Publication number
WO2015150948A1
WO2015150948A1 PCT/IB2015/051942 IB2015051942W WO2015150948A1 WO 2015150948 A1 WO2015150948 A1 WO 2015150948A1 IB 2015051942 W IB2015051942 W IB 2015051942W WO 2015150948 A1 WO2015150948 A1 WO 2015150948A1
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WO
WIPO (PCT)
Prior art keywords
cyclobenzaprine
salt
solid oral
pharmaceutical composition
oral pharmaceutical
Prior art date
Application number
PCT/IB2015/051942
Other languages
French (fr)
Inventor
Moinuddin SYED
Vishal Omprakash DAGA
Rahul Sudhakar Dabre
Girish Kumar Jain
Original Assignee
Wockhardt Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Priority claimed from IN1187MU2014 external-priority patent/IN2014MU01187A/en
Priority claimed from IN1185MU2014 external-priority patent/IN2014MU01185A/en
Priority claimed from IN1186MU2014 external-priority patent/IN2014MU01186A/en
Priority claimed from IN1184MU2014 external-priority patent/IN2014MU01184A/en
Publication of WO2015150948A1 publication Critical patent/WO2015150948A1/en

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Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention provides a modified release solid oral pharmaceutical composition comprising cyclobenzaprine or salt thereof.
  • the present invention relates to modified release solid oral pharmaceutical composition comprising a core comprising cyclobenzaprine or a salt thereof and one or more release modifying substances, which core is coated with one or more water soluble and/ or water insoluble release modifying polymers.
  • the composition may provide extended and specific release of cyclobenzaprine or a salt thereof to achieve therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof.
  • the invention also includes process of preparing such composition.
  • a spasm is a sudden, involuntary contraction of a muscle, a group of muscles. It most commonly refers to a muscle cramp which is often accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes. There is a variety of other causes of involuntary muscle contractions, which may be more serious, depending on the cause.
  • the spasm may also refer to a temporary burst of energy, activity, emotion, eustress, stress, or anxiety unrelated to, or as a consequence of, involuntary muscle activity.
  • spasmodic muscle contraction may be due to a large number of medical conditions, including the dystonias.
  • a hypertonic muscle spasm is the state of chronic, excessive muscle tone, or tension in a resting muscle (the amount of contraction that remains when a muscle is not actively working).
  • a muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia.
  • Cyclobenzaprine functions as a muscle relaxant by blocking nerve impulses (or pain sensations) that are sent to your brain. Cyclobenzaprine is used together with rest and physical therapy to treat skeletal muscle conditions such as pain or injury.
  • Cyclobenzaprine is a tricyclic class of antidepressant, skeletal muscle relaxant. It is a white, crystalline tricyclic amine salt with the empirical formula C20H21 N.HCI and a molecular weight of 31 1 .9 and is designated chemically as 3-(5H-dibenzo [a, d] cyclohepten-5-ylidene)-N, N-dimethyl-1 -propanamine and has the following structural formula:
  • Cyclobenzaprine is one of the routinely prescribed muscle relaxant approved and marketed in United States under the proprietary name Amrix ® as extended release capsule by Teva.
  • Amrix ® is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions.
  • active pharmaceutical agents have been formulated as orally administrable extended release (over a period of time) dosage form to permit once daily administration.
  • the extended release of drug can be achieved either by coating the composition with release modifying substance or by dispersing drug in a matrix comprising one or more release modifying substances, In case of matrix-type dosage form, the drug is released over a period of time in the gastrointestinal tract upon erosion of the matrix.
  • Extended-release dosage forms comprising a matrix system are conveniently prepared as compressed tablets.
  • drugs having relatively high solubility in water for example a solubility of about 10 mg/ml or greater, present challenges to the formulator wishing to provide an extended-release dosage form and the higher the solubility greater are the challenges.
  • U.S. Patent No. 5,582,838 discloses a drug delivery device for the controlled release of a beneficial agent.
  • the drug delivery device includes a compressed core having at least two layers: at least one layer is a mixture of a beneficial agent and a polymer which forms microscopic polymer gel beads upon hydration and at least one outer layer comprises a polymer which forms microscopic polymer gel beads upon hydration.
  • Water insoluble, water impermeable coating is applied to the core and the coating has apertures exposing between about 5-75% of the core surface.
  • PCT publication No. WO 2004/016249 discloses extended release matrix tablets for oral administration that include a cationic polymer, a water-swellable polymer, and an alginic acid derivative to cause the release rate of the active ingredient of the tablets to be independent of pH and gastric residence time.
  • PCT publication No. WO 2010/133961 discloses extended release pharmaceutical compositions comprising cyclobenzaprine or a salt thereof in the form of an inert core coated with matrix type extended release layer.
  • the drug may be coated onto inert core or may be present in matrix type extended release layer.
  • PCT publication No. WO 98/18610 discloses controlled release particles containing an active agent without substantial destruction of the matrix material.
  • a release-rate controlling component is incorporated in a matrix to control the release rate of the encapsulant from the particles.
  • a hydrophobic component or a high water binding capacity component may be used for extending the release time.
  • PCT publication No. WO 98/06439 discloses a composition comprising dug encapsulated in a matrix comprising a polyether ester copolymer, such as polyethylene glycol terephthalate/polybutylene-terephthalate copolymer. The polyether ester copolymer protects the active agent from degradation and thereby facilitates the drug delivery.
  • U.S. Patent No. 7,387,793 discloses modified release dosage forms wherein cyclobenzaprine extended release beads comprises active-containing core particle and an extended release coating of a water insoluble polymer membrane surrounding said core.
  • Pellets provide desired release profile based on the amount and type of coating of release modifying substances. But the peptization is sophisticated techniques which requires high end manufacturing facilities and add complexity to production process while consuming much of time and resources.
  • compositions comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances, which may provide therapeutically effective plasma concentration over a period of 24 hours.
  • Such compositions can be used to treat muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof.
  • a modified release solid oral pharmaceutical composition comprising:
  • a modified release solid oral pharmaceutical composition comprising:
  • a modified release solid oral pharmaceutical composition comprising:
  • a modified release solid oral pharmaceutical composition wherein cyclobenzaprine or a salt thereof is dispersed in the matrix of one or more release modifying substances and at least one pharmaceutically acceptable excipient to form a core, which core is coated with one or more water insoluble release modifying substances; wherein the coating is devoid of water soluble substances.
  • the core may be in the form of granules or minitablets.
  • the composition may contain only one such coated minitablet.
  • composition may contain one or more such coated cores.
  • a modified release solid oral pharmaceutical composition wherein the coated core has dimension of more than 0.5 mm, preferably more than 1 .0 mm and more preferably more than 2.0 mm.
  • a modified release solid oral pharmaceutical composition wherein the ratio of amount of cyclobenzaprine or a salt thereof and release modifying substances in the core is in the range of about 1 :1 to about 1 :5.
  • a modified release solid oral pharmaceutical composition wherein the ratio of amount of cyclobenzaprine or a salt thereof and water insoluble release modifying in the coating is in the range of about 10:1 to about 2:1 .
  • a modified release solid oral pharmaceutical composition wherein the ratio of amount of cyclobenzaprine or a salt thereof and water soluble release modifying in the coating is in the range of about 10:1 to about 2:1 .
  • the composition contains one or more coated cores filled in a hard gelatin capsule.
  • a modified release solid oral pharmaceutical composition wherein the capsule comprises about 0.1 % w/w to about 95% w/w, preferably of about 5% w/w to about 85% w/w of cyclobenzaprine or salt thereof.
  • a modified release solid oral pharmaceutical composition wherein the amount of release modifying substances in the dosage form ranges from about 5% w/w to about 95% w/w, preferably about 15% w/w to about 85% w/w of the composition.
  • a modified release solid oral pharmaceutical composition comprising one or more release modifying substances and one or more pharmaceutically acceptable excipients selected from, but not limited to diluent, binder, disintegrant, stabilizing agent, glidant, lubricant, and flavoring agents.
  • step (b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant
  • step (c) compressing the lubricated granules of step (b) to form a core
  • step (d) coating the core of step (c) with one or more water insoluble release modifying substances
  • the coating is devoid of water soluble substances.
  • a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of: (a) granulating the dry blend comprising cyclobenzaprine or salt thereof, hypromellose, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form core
  • step (d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate;
  • the coating is devoid of water soluble substances.
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form core;
  • step (d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate;
  • step (e) filling one or more coated cores of step (d) in a capsule
  • the coating is devoid of water soluble substances.
  • step (b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant
  • step (c) compressing the lubricated granules of step (b) to form a core
  • step (d) coating the core of step (c) with one or more water soluble release modifying substances
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form a core
  • step (d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, talc and titanium dioxide;
  • the coating is devoid of water insoluble substances.
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form core;
  • step (d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, talc and titanium dioxide to form a coated core, and
  • step (e) filling the coated core of step (d) in a capsule
  • the coating is devoid of water insoluble substances.
  • a method of treating muscle spasm associated with acute, painful musculoskeletal conditions by administering a modified release solid oral pharmaceutical composition comprising cyclobenzapnne or a salt thereof in accordance of the present invention.
  • a modified release solid oral pharmaceutical composition wherein the composition exhibits a release profile such that not more than about 40% of cyclobenzapnne or a salt thereof is released in 2 hours, not less than 40% of cyclobenzapnne or a salt thereof is released in 4 hours and not less than 60% of cyclobenzaprine or a salt thereof is released in 8 hours when measured in 900 ml_ of 0.1 N HCI at 37°C using USP Type II dissolution apparatus.
  • the modified release solid oral pharmaceutical composition may provide therapeutically effective plasma concentration of cyclobenzaprine or a salt thereof over a period of 24 hours.
  • a modified release solid oral pharmaceutical composition characterized in that the dosage form is bioequivalent to the formulation of cyclobenzaprine marketed under the brand/trade name Amrix ® .
  • a modified release solid oral pharmaceutical composition that retains at least 90% w/w of the potency of cyclobenzaprine or a salt thereof when stored at 25°C and 40% relative humidity or at 40°C and 25% relative humidity for 3 months.
  • a method of substantially minimizing the intersubject variability and improving the quality of life, especially in the elderly population comprises administering the composition comprising cyclobenzaprine or a salt thereof prepared in accordance of the present invention.
  • the present invention relates to a modified release solid oral pharmaceutical composition for delivering cyclobenzaprine or a salt thereof by modifying the release.
  • cyclobenzaprine is dispersed in the matrix of one or more release modifying substances and one or more pharmaceutically acceptable excipients.
  • the composition is coated with water soluble and/ or water insoluble release modifying substances.
  • Such compositions may provide an extended release profile of cyclobenzaprine under in vitro conditions and may provide effective plasma concentration over a period of 24 hours.
  • Such compositions can be used for treating muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof.
  • cyclobenzaprine used throughout the specification refers to not only cyclobenzaprine per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
  • modified release used throughout the specification shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner.
  • Types of modified release include controlled, prolonged, sustained, extended, delayed, and the likes.
  • matrix used throughout the specification refers to the dispersion of cyclobenzaprine within one or more release modifying substances and optionally one or more pharmaceutical excipients, or mixture thereof.
  • pharmaceutically acceptable excipients includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject/person/patient to whom it will be administered. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.
  • the release modifying substances used for preparing a matrix core of cyclobenzaprine or a salt thereof include both water soluble and water insoluble release modifying substances.
  • the release modifying substances or substancesused for coating the core comprising cyclobenzaprine or a salt thereof does not include any water insoluble substances.
  • the release modifying substances which can be used for preparing a matrix core of cyclobenzaprine or a salt thereof may be selected from the group consisting of hydrophilic agents (e.g.
  • hydrophilic agents are selected from the group of pharmaceutical excipients which generate a gel in contact with water, including cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like; noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers, polyethylene oxide and mixtures thereof; the lipophilic agents are selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol,
  • thermoplastic polymers which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.
  • the water soluble release modifying substances which can be used for coating a matrix core of cyclobenzaprine or a salt thereof may be selected from the group consisting of substances such as water soluble grades of low viscosity hydroxypropyl methyl cellulose and hydroxypropyl cellulose, water soluble noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers and mixtures thereof; water soluble grades of acrylic acid polymers and copolymers (available commercially under Eudragit ® brand); and mixtures thereof.
  • substances such as water soluble grades of low viscosity hydroxypropyl methyl cellulose and hydroxypropyl cellulose, water soluble noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, algina
  • the water insoluble release modifying substances which can be used for coating a matrix core of cyclobenzaprine or a salt thereof may be selected from the group consisting of substances such as water insoluble grades of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g.
  • Diluents increase the bulk of a solid pharmaceutical composition.
  • Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • Solid pharmaceutical compositions that are compressed may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression which are know as binders.
  • binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate and starch.
  • Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example.
  • Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • exemplary excipients that may function as glidants include, but not limited to colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • exemplary lubricants include, but are not limited to magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • the modified release solid oral pharmaceutical composition comprising:
  • modified release solid oral pharmaceutical composition comprising:
  • the coating is devoid of water soluble substances.
  • modified release solid oral pharmaceutical composition comprising:
  • the core may be in the form of granules or minitablet.
  • the modified release solid oral pharmaceutical composition comprises of one or more cores.
  • the modified release solid oral pharmaceutical composition wherein one or more coated cores are filled in a capsule.
  • the modified release solid oral pharmaceutical composition wherein the ratio of amount of cyclobenzapnne or a salt thereof and release modifying substances is in the range of about 1 :1 to about 1 :5.
  • the modified release solid oral pharmaceutical composition wherein the ratio of amount of cyclobenzapnne or a salt thereof and water soluble release modifying substances is in the range of about 10:1 to about 2:1 .
  • the modified release solid oral pharmaceutical composition wherein the ratio of amount of cyclobenzapnne or a salt thereof and water soluble release modifying substances in the coating is in the range of about 10:1 to about 2:1 .
  • the modified release solid oral pharmaceutical composition wherein the capsule comprises about 0.1 % w/w to about 95% w/w, preferably of about 5% w/w to about 85% w/w of cyclobenzaprine or salt thereof.
  • the modified release solid oral pharmaceutical composition wherein the amount of release modifying substances in the dosage form ranges from about 5% w/w to about 95% w/w, preferably about 15% w/w to about 85% w/w of the composition.
  • step (b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant
  • step (c) compressing the lubricated granules of step (b) to form a core
  • step (d) coating the core of step (c) with one or more water soluble and/ or water insoluble release modifying substances to form a coated core.
  • step (b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant
  • step (c) compressing the lubricated granules of step (b) to form a core; and (d) coating the core of step (c) with one or more water soluble release modifying substances to form a coated core,
  • the coating is devoid of water insoluble release modifying substances.
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form a core
  • step (d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, talc and titanium dioxide to form a coated core
  • the coating is devoid of water insoluble substances.
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form core;
  • step (d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, tal and titanium dioxide to form a coated core;
  • step (e) filling the coated core of step (d) in a capsule
  • the coating is devoid of water insoluble substances.
  • modified release solid oral pharmaceutical composition comprising steps of:
  • step (b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant; (c) compressing the lubricated granules of step (b) to form a core, and
  • step (d) coating the core of step (c) with one or more water insoluble release modifying substances
  • the coating is devoid of water soluble substances.
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form core
  • step (d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate;
  • the coating is devoid of water soluble substances.
  • step (b) lubricating the granules of step (a) with magnesium stearate;
  • step (c) compressing the lubricated granules of step (b) to form core;
  • step (d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate;
  • step (e) filling one or more coated cores of step (d) in a capsule
  • the coating is devoid of water soluble substances.
  • the method of treating muscle spasm associated with acute, painful musculoskeletal conditions by administering a modified release solid oral pharmaceutical composition comprising cyclobenzaprine or a salt thereof in accordance of the present invention.
  • a modified release solid oral pharmaceutical composition wherein the composition exhibits a release profile such that not more than about 40% of cyclobenzapnne or a salt thereof is released in 2 hours, not less than 40% of cyclobenzapnne or a salt thereof is released in 4 hours and not less than 60% of cyclobenzapnne or a salt thereof is released in 8 hours when measured in 900 ml_ of 0.1 N HCI at 37°C using USP Type II dissolution apparatus.
  • the modified release solid oral pharmaceutical composition may provide therapeutically effective plasma concentration of cyclobenzapnne or a salt thereof over a period of 24 hours.
  • the modified release solid oral pharmaceutical composition characterized in that the dosage form is bioequivalent to the formulation of cyclobenzaprine marketed under the trade name Amrix ® .
  • the modified release solid oral pharmaceutical composition that retains at least 90% w/w of the potency of cyclobenzaprine or a salt thereof when stored at 25°C and 40% relative humidity or at 40°C and 25% relative humidity for 3 months.
  • the method of substantially minimizing the intersubject variability and improving the quality of life, especially in the elderly population comprises administering the composition comprising cyclobenzaprine or a salt thereof prepared in accordance of the present invention.
  • the modified release unit dosage form of cyclobenzaprine or a salt thereof may be developed in the form a capsule, a tablet, a caplet and a mini-tablet.
  • the dosage form is in the form of a capsule.
  • composition of the present invention may comprise one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, glidant, lubricant, stabilizing agent, and flavoring agents; wherein the composition is coated with a coating devoid of water insoluble substances.
  • the present invention further provides a method of treating muscle spasm associated with acute, painful musculoskeletal conditions by administering the modified release solid oral pharmaceutical composition comprising cyclobenzapnne or a salt thereof as substantially described throughout the specification.
  • the present invention further provides a method of substantially minimizing the intersubject variability and improving the quality of life, especially in the elderly population, which method comprises administering a modified release unit dosage form of cyclobenzapnne or a salt thereof as substantially described throughout the specification.
  • Cyclobenzaprine hydrochloride, hypromellose 2208, lactose monohydrate and microcrystalline cellulose were sifted and mixed to form dry powder blend.
  • dry powder blend was granulated using purified water to form granules.
  • the obtained granules were dried and milled.
  • the granules were lubricated with magnesium stearate and compressed to form core mini-tablets.
  • the tablets were coated with a water insoluble coating composition comprising ethylcellulose, polyvinyl pyrrolidone and triethyl citrate and a single unit mini-tablet was filled in hard gelatin capsule.

Abstract

The present invention provides a modified release solid oral pharmaceutical composition comprising cyclobenzaprine or salt thereof. In particular, the present invention relates to modified release solid oral pharmaceutical composition comprising a core comprising cyclobenzaprine or a salt thereof and one or more release modifying substances, which core is coated with one or more water soluble and/ or water insoluble release modifying polymers. The composition may provide extended and specific release of cyclobenzaprine or a salt thereof to achieve therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof. The invention also includes process of preparing such composition.

Description

MODIFIED RELEASE SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF CYCLOBENZAPRINE OR A SALT THEREOF
Field of the Invention
The present invention provides a modified release solid oral pharmaceutical composition comprising cyclobenzaprine or salt thereof. In particular, the present invention relates to modified release solid oral pharmaceutical composition comprising a core comprising cyclobenzaprine or a salt thereof and one or more release modifying substances, which core is coated with one or more water soluble and/ or water insoluble release modifying polymers. The composition may provide extended and specific release of cyclobenzaprine or a salt thereof to achieve therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof. The invention also includes process of preparing such composition.
Background of the Invention
A spasm is a sudden, involuntary contraction of a muscle, a group of muscles. It most commonly refers to a muscle cramp which is often accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes. There is a variety of other causes of involuntary muscle contractions, which may be more serious, depending on the cause. The spasm may also refer to a temporary burst of energy, activity, emotion, eustress, stress, or anxiety unrelated to, or as a consequence of, involuntary muscle activity.
Amongst causes of spasms are insufficient hydration, muscle overload, and absence of electrolytes. Spasmodic muscle contraction may be due to a large number of medical conditions, including the dystonias. A hypertonic muscle spasm is the state of chronic, excessive muscle tone, or tension in a resting muscle (the amount of contraction that remains when a muscle is not actively working). A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. Cyclobenzaprine functions as a muscle relaxant by blocking nerve impulses (or pain sensations) that are sent to your brain. Cyclobenzaprine is used together with rest and physical therapy to treat skeletal muscle conditions such as pain or injury.
Cyclobenzaprine is a tricyclic class of antidepressant, skeletal muscle relaxant. It is a white, crystalline tricyclic amine salt with the empirical formula C20H21 N.HCI and a molecular weight of 31 1 .9 and is designated chemically as 3-(5H-dibenzo [a, d] cyclohepten-5-ylidene)-N, N-dimethyl-1 -propanamine and has the following structural formula:
Figure imgf000003_0001
Cyclobenzaprine is one of the routinely prescribed muscle relaxant approved and marketed in United States under the proprietary name Amrix® as extended release capsule by Teva.
Amrix® is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions.
Many active pharmaceutical agents have been formulated as orally administrable extended release (over a period of time) dosage form to permit once daily administration. The extended release of drug can be achieved either by coating the composition with release modifying substance or by dispersing drug in a matrix comprising one or more release modifying substances, In case of matrix-type dosage form, the drug is released over a period of time in the gastrointestinal tract upon erosion of the matrix.
Extended-release dosage forms comprising a matrix system are conveniently prepared as compressed tablets. But drugs having relatively high solubility in water, for example a solubility of about 10 mg/ml or greater, present challenges to the formulator wishing to provide an extended-release dosage form and the higher the solubility greater are the challenges.
U.S. Patent No. 5,582,838 discloses a drug delivery device for the controlled release of a beneficial agent. The drug delivery device includes a compressed core having at least two layers: at least one layer is a mixture of a beneficial agent and a polymer which forms microscopic polymer gel beads upon hydration and at least one outer layer comprises a polymer which forms microscopic polymer gel beads upon hydration. Water insoluble, water impermeable coating is applied to the core and the coating has apertures exposing between about 5-75% of the core surface.
PCT publication No. WO 2004/016249 discloses extended release matrix tablets for oral administration that include a cationic polymer, a water-swellable polymer, and an alginic acid derivative to cause the release rate of the active ingredient of the tablets to be independent of pH and gastric residence time.
PCT publication No. WO 2010/133961 discloses extended release pharmaceutical compositions comprising cyclobenzaprine or a salt thereof in the form of an inert core coated with matrix type extended release layer. The drug may be coated onto inert core or may be present in matrix type extended release layer.
PCT publication No. WO 98/18610 discloses controlled release particles containing an active agent without substantial destruction of the matrix material. A release-rate controlling component is incorporated in a matrix to control the release rate of the encapsulant from the particles. A hydrophobic component or a high water binding capacity component may be used for extending the release time. PCT publication No. WO 98/06439 discloses a composition comprising dug encapsulated in a matrix comprising a polyether ester copolymer, such as polyethylene glycol terephthalate/polybutylene-terephthalate copolymer. The polyether ester copolymer protects the active agent from degradation and thereby facilitates the drug delivery.
U.S. Patent No. 7,387,793 discloses modified release dosage forms wherein cyclobenzaprine extended release beads comprises active-containing core particle and an extended release coating of a water insoluble polymer membrane surrounding said core.
Several prior art references disclose different dosage forms wherein the active ingredient containing core/pellets/beads/matrix tablets were coated with water insoluble release modifying polymers.
Pellets provide desired release profile based on the amount and type of coating of release modifying substances. But the peptization is sophisticated techniques which requires high end manufacturing facilities and add complexity to production process while consuming much of time and resources.
Thus, there exists an enduring need to develop an improved modified release simple pharmaceutical composition of cyclobenzaprine which may provide an alternative to existing formulations to provide relief of muscle spasm associated with painful musculoskeletal conditions over a 24 hour period.
Also there exists a need to develop modified release pharmaceutical composition of cyclobenzaprine by using simple and economical process.
The inventors of the present invention have surprisingly found that it is possible to devise a composition comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances, which may provide therapeutically effective plasma concentration over a period of 24 hours. Such compositions can be used to treat muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof.
Summary of the Invention
In one general aspect, there is provided a modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances; and
(b) a coating comprising one or more water soluble and/ or water insoluble release modifying substances.
substances
In another general aspect, there is provided a modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances; and
(b) a coating comprising one or more water insoluble release modifying substances, wherein the coating is devoid of water soluble substances.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances; and
(b) a coating comprising one or more water soluble release modifying substances, wherein the coating is devoid of water insoluble substances.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein cyclobenzaprine or a salt thereof is dispersed in the matrix of one or more release modifying substances and at least one pharmaceutically acceptable excipient to form a core, which core is coated with one or more water insoluble release modifying substances; wherein the coating is devoid of water soluble substances.
In another general aspect, the core may be in the form of granules or minitablets.
In another general aspect, the composition may contain only one such coated minitablet.
In another general aspect, the composition may contain one or more such coated cores.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein the coated core has dimension of more than 0.5 mm, preferably more than 1 .0 mm and more preferably more than 2.0 mm.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein the ratio of amount of cyclobenzaprine or a salt thereof and release modifying substances in the core is in the range of about 1 :1 to about 1 :5.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein the ratio of amount of cyclobenzaprine or a salt thereof and water insoluble release modifying in the coating is in the range of about 10:1 to about 2:1 .
In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein the ratio of amount of cyclobenzaprine or a salt thereof and water soluble release modifying in the coating is in the range of about 10:1 to about 2:1 .
In another general aspect, the composition contains one or more coated cores filled in a hard gelatin capsule. In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein the capsule comprises about 0.1 % w/w to about 95% w/w, preferably of about 5% w/w to about 85% w/w of cyclobenzaprine or salt thereof.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein the amount of release modifying substances in the dosage form ranges from about 5% w/w to about 95% w/w, preferably about 15% w/w to about 85% w/w of the composition.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition comprising one or more release modifying substances and one or more pharmaceutically acceptable excipients selected from, but not limited to diluent, binder, disintegrant, stabilizing agent, glidant, lubricant, and flavoring agents.
In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one or more release modifying substance and at least one or more pharmaceutically acceptable excipient with purified water to form granules;
(b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant;
(c) compressing the lubricated granules of step (b) to form a core, and
(d) coating the core of step (c) with one or more water insoluble release modifying substances,
wherein the coating is devoid of water soluble substances.
In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of: (a) granulating the dry blend comprising cyclobenzaprine or salt thereof, hypromellose, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form core, and
(d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate;
wherein the coating is devoid of water soluble substances.
In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating the dry blend comprising cyclobenzaprine or salt thereof, hypromellose, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form core;
(d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate; and
(e) filling one or more coated cores of step (d) in a capsule,
wherein the coating is devoid of water soluble substances.
In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one or more release modifying substance and at least one or more pharmaceutically acceptable excipient with purified water to form granules;
(b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant;
(c) compressing the lubricated granules of step (b) to form a core, and
(d) coating the core of step (c) with one or more water soluble release modifying substances,
wherein the coating is devoid of water insoluble substances. In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating the dry blend comprising cyclobenzapnne or salt thereof, hypromellose, methacrylic acid copolymer, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form a core, and
(d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, talc and titanium dioxide;
wherein the coating is devoid of water insoluble substances.
In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating the dry blend comprising cyclobenzapnne or salt thereof, hypromellose, methacrylic acid copolymer, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form core;
(d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, talc and titanium dioxide to form a coated core, and
(e) filling the coated core of step (d) in a capsule,
wherein the coating is devoid of water insoluble substances.
In another general aspect, there is provided a method of treating muscle spasm associated with acute, painful musculoskeletal conditions by administering a modified release solid oral pharmaceutical composition comprising cyclobenzapnne or a salt thereof in accordance of the present invention.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition; wherein the composition exhibits a release profile such that not more than about 40% of cyclobenzapnne or a salt thereof is released in 2 hours, not less than 40% of cyclobenzapnne or a salt thereof is released in 4 hours and not less than 60% of cyclobenzaprine or a salt thereof is released in 8 hours when measured in 900 ml_ of 0.1 N HCI at 37°C using USP Type II dissolution apparatus.
The modified release solid oral pharmaceutical composition may provide therapeutically effective plasma concentration of cyclobenzaprine or a salt thereof over a period of 24 hours.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition characterized in that the dosage form is bioequivalent to the formulation of cyclobenzaprine marketed under the brand/trade name Amrix®.
In another general aspect, there is provided a modified release solid oral pharmaceutical composition that retains at least 90% w/w of the potency of cyclobenzaprine or a salt thereof when stored at 25°C and 40% relative humidity or at 40°C and 25% relative humidity for 3 months.
In another general aspect, there is provided a method of substantially minimizing the intersubject variability and improving the quality of life, especially in the elderly population, which method comprises administering the composition comprising cyclobenzaprine or a salt thereof prepared in accordance of the present invention.
Detailed Description of the Invention
The present invention relates to a modified release solid oral pharmaceutical composition for delivering cyclobenzaprine or a salt thereof by modifying the release. Preferably, cyclobenzaprine is dispersed in the matrix of one or more release modifying substances and one or more pharmaceutically acceptable excipients. The composition is coated with water soluble and/ or water insoluble release modifying substances. Such compositions may provide an extended release profile of cyclobenzaprine under in vitro conditions and may provide effective plasma concentration over a period of 24 hours. Such compositions can be used for treating muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof.
The term "cyclobenzaprine" used throughout the specification refers to not only cyclobenzaprine per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
The term "modified release" used throughout the specification shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner. Types of modified release include controlled, prolonged, sustained, extended, delayed, and the likes.
The term "matrix" used throughout the specification refers to the dispersion of cyclobenzaprine within one or more release modifying substances and optionally one or more pharmaceutical excipients, or mixture thereof.
The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject/person/patient to whom it will be administered. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.
The release modifying substances used for preparing a matrix core of cyclobenzaprine or a salt thereof include both water soluble and water insoluble release modifying substances.
The release modifying substances or substancesused for coating the core comprising cyclobenzaprine or a salt thereof does not include any water insoluble substances. The release modifying substances which can be used for preparing a matrix core of cyclobenzaprine or a salt thereof may be selected from the group consisting of hydrophilic agents (e.g. water soluble polymers), lipophilic agents (water insoluble polymers) and inert matrix agents, wherein the hydrophilic agents are selected from the group of pharmaceutical excipients which generate a gel in contact with water, including cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like; noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers, polyethylene oxide and mixtures thereof; the lipophilic agents are selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable oil, castor oil, cottonseed oil, glyceril behenate and the like; ethyl cellulose; acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof; and the inert agents are selected from the group consisting of thermoplastic polymers, which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.
The water soluble release modifying substances which can be used for coating a matrix core of cyclobenzaprine or a salt thereof may be selected from the group consisting of substances such as water soluble grades of low viscosity hydroxypropyl methyl cellulose and hydroxypropyl cellulose, water soluble noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers and mixtures thereof; water soluble grades of acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof.
The water insoluble release modifying substances which can be used for coating a matrix core of cyclobenzaprine or a salt thereof may be selected from the group consisting of substances such as water insoluble grades of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable oil, castor oil, cottonseed oil, glyceril behenate and the like; ethyl cellulose; acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof.
Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compressed may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression which are know as binders. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate and starch. Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include, but not limited to colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
In one embodiment, the modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances; and
(b) a coating comprising of one or more water soluble and/ or water insoluble release modifying substances.
In another embodiment, the modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances; and (b) a coating comprising of one or more water insoluble release modifying substances;
wherein the coating is devoid of water soluble substances.
In another embodiment, the modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzapnne or a salt thereof in a matrix of one or more release modifying substances; and
(b) a coating comprising of one or more water soluble release modifying substances; wherein the coating is devoid of water insoluble substances.
In an embodiment, the core may be in the form of granules or minitablet.
In an embodiment, the modified release solid oral pharmaceutical composition comprises of one or more cores.
In another embodiment, the modified release solid oral pharmaceutical composition; wherein one or more coated cores are filled in a capsule.
In an embodiment, the modified release solid oral pharmaceutical composition; wherein the ratio of amount of cyclobenzapnne or a salt thereof and release modifying substances is in the range of about 1 :1 to about 1 :5.
In an embodiment, the modified release solid oral pharmaceutical composition; wherein the ratio of amount of cyclobenzapnne or a salt thereof and water soluble release modifying substances is in the range of about 10:1 to about 2:1 .
In an embodiment, the modified release solid oral pharmaceutical composition; wherein the ratio of amount of cyclobenzapnne or a salt thereof and water soluble release modifying substances in the coating is in the range of about 10:1 to about 2:1 . In another embodiment, the modified release solid oral pharmaceutical composition; wherein the core has dimension of more than 0.5 mm, particularly more than 1 .0 mm and preferably more than 2.0 mm.
In another embodiment, the modified release solid oral pharmaceutical composition; wherein the capsule comprises about 0.1 % w/w to about 95% w/w, preferably of about 5% w/w to about 85% w/w of cyclobenzaprine or salt thereof.
In another embodiment, the modified release solid oral pharmaceutical composition; wherein the amount of release modifying substances in the dosage form ranges from about 5% w/w to about 95% w/w, preferably about 15% w/w to about 85% w/w of the composition.
In another embodiment, the process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one release modifying substance and at least one pharmaceutically acceptable excipient with purified water to form granules;
(b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant;
(c) compressing the lubricated granules of step (b) to form a core; and
(d) coating the core of step (c) with one or more water soluble and/ or water insoluble release modifying substances to form a coated core.
In another embodiment, the process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one release modifying substance and at least one pharmaceutically acceptable excipient with purified water to form granules;
(b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant;
(c) compressing the lubricated granules of step (b) to form a core; and (d) coating the core of step (c) with one or more water soluble release modifying substances to form a coated core,
wherein the coating is devoid of water insoluble release modifying substances.
In another embodiment, the process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating the dry blend comprising cyclobenzaprine or salt thereof, hypromellose, methacrylic acid copolymer, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form a core; and
(d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, talc and titanium dioxide to form a coated core
wherein the coating is devoid of water insoluble substances.
In another embodiment, the process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating the dry blend comprising cyclobenzaprine or salt thereof, hypromellose, methacrylic acid copolymer, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form core;
(d) coating the core of step (c) with a composition comprising hypromellose 5 cps, polyethylene glycol, tal and titanium dioxide to form a coated core; and
(e) filling the coated core of step (d) in a capsule
wherein the coating is devoid of water insoluble substances.
In another embodiment, the modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one or more release modifying substance and at least one or more pharmaceutically acceptable excipient with purified water to form granules;
(b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant; (c) compressing the lubricated granules of step (b) to form a core, and
(d) coating the core of step (c) with one or more water insoluble release modifying substances,
wherein the coating is devoid of water soluble substances.
In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating the dry blend comprising cyclobenzaprine or salt thereof, hypromellose, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form core, and
(d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate;
wherein the coating is devoid of water soluble substances.
In another general aspect, there is provided a process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating the dry blend comprising cyclobenzaprine or salt thereof, hypromellose, lactose monohydrate and microcrystalline cellulose with purified water to form granules;
(b) lubricating the granules of step (a) with magnesium stearate;
(c) compressing the lubricated granules of step (b) to form core;
(d) coating the core of step (c) with a composition comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate; and
(e) filling one or more coated cores of step (d) in a capsule,
wherein the coating is devoid of water soluble substances.
In another embodiment, the method of treating muscle spasm associated with acute, painful musculoskeletal conditions by administering a modified release solid oral pharmaceutical composition comprising cyclobenzaprine or a salt thereof in accordance of the present invention. In another embodiment, the a modified release solid oral pharmaceutical composition; wherein the composition exhibits a release profile such that not more than about 40% of cyclobenzapnne or a salt thereof is released in 2 hours, not less than 40% of cyclobenzapnne or a salt thereof is released in 4 hours and not less than 60% of cyclobenzapnne or a salt thereof is released in 8 hours when measured in 900 ml_ of 0.1 N HCI at 37°C using USP Type II dissolution apparatus.
The modified release solid oral pharmaceutical composition may provide therapeutically effective plasma concentration of cyclobenzapnne or a salt thereof over a period of 24 hours.
In another embodiment, the modified release solid oral pharmaceutical composition characterized in that the dosage form is bioequivalent to the formulation of cyclobenzaprine marketed under the trade name Amrix®.
In another embodiment, the modified release solid oral pharmaceutical composition that retains at least 90% w/w of the potency of cyclobenzaprine or a salt thereof when stored at 25°C and 40% relative humidity or at 40°C and 25% relative humidity for 3 months.
In another embodiment, the method of substantially minimizing the intersubject variability and improving the quality of life, especially in the elderly population, which method comprises administering the composition comprising cyclobenzaprine or a salt thereof prepared in accordance of the present invention.
The modified release unit dosage form of cyclobenzaprine or a salt thereof may be developed in the form a capsule, a tablet, a caplet and a mini-tablet. Preferably the dosage form is in the form of a capsule.
The composition of the present invention may comprise one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, glidant, lubricant, stabilizing agent, and flavoring agents; wherein the composition is coated with a coating devoid of water insoluble substances.
The present invention further provides a method of treating muscle spasm associated with acute, painful musculoskeletal conditions by administering the modified release solid oral pharmaceutical composition comprising cyclobenzapnne or a salt thereof as substantially described throughout the specification.
The present invention further provides a method of substantially minimizing the intersubject variability and improving the quality of life, especially in the elderly population, which method comprises administering a modified release unit dosage form of cyclobenzapnne or a salt thereof as substantially described throughout the specification.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 : Cyclobenzaprine HCI Capsule
Table 1
Figure imgf000022_0001
Process: Cyclobenzaprine hydrochloride, hypromellose 2208, lactose monohydrate, microcrystalline cellulose and methacrylic acid copolymer were sifted and mixed to form dry powder blend. Thus formed dry powder blend was granulated using purified water to form granules. The obtained granules were dried and milled. The granules were lubricated with magnesium stearate and compressed to form core tablets. The core tablets were coated with opadry white comprising hypromellose 5 cps. The two minitablets were filled in each hard gelatin capsules. Example 2: Cyclobenzaprine HCI Capsule
Table 2
Figure imgf000023_0001
Process: Cyclobenzaprine hydrochloride, hypromellose 2208, lactose monohydrate and microcrystalline cellulose were sifted and mixed to form dry powder blend. Thus formed dry powder blend was granulated using purified water to form granules. The obtained granules were dried and milled. The granules were lubricated with magnesium stearate and compressed to form core mini-tablets. The tablets were coated with a water insoluble coating composition comprising ethylcellulose, polyvinyl pyrrolidone and triethyl citrate and a single unit mini-tablet was filled in hard gelatin capsule.
Dissolution Studies in 0.1 N HCI. 900 ml (USP type II: 50 rpm): Table 3
Figure imgf000024_0003
Bioequivalence Studies: Fasting: Tablets of Example 1 (Test A) and Tablets of Example 2 (Test B) versus Innovator (Ref C)
Table 4
Figure imgf000024_0001
Table 5
Figure imgf000024_0002

Claims

Claims:
1 . A modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix with one or more release modifying substances, and
(b) a coating comprising of one or more water soluble and/ or water insoluble release modifying substances.
2. A modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances, and
(b) a coating comprising of one or more water soluble release modifying substances;
wherein the coating is devoid of water insoluble substances.
3. A modified release solid oral pharmaceutical composition comprising:
(a) a core comprising cyclobenzaprine or a salt thereof in a matrix of one or more release modifying substances, and
(b) a coating comprising of one or more water insoluble release modifying substances;
wherein the coating is devoid of water soluble substances.
4. The modified release solid oral pharmaceutical composition of claim 1 , 2 or 3, wherein the core is in the form of granules or minitablet.
5. The modified release solid oral pharmaceutical composition of claim 1 , 2 or 3, wherein the composition comprises one or more cores.
6. The modified release solid oral pharmaceutical composition of claim 1 , 2 or 3, wherein the composition of claim 1 , 2 or 3 is filled in a hard gelatin capsule.
7. The modified release solid oral pharmaceutical composition of claim 1 , 2 or 3; wherein the core has dimension of more than 0.5 mm.
8. The modified release solid oral pharmaceutical composition of claim 1 , wherein the ratio of amount of cyclobenzaprine or a salt thereof and release modifying substances in the composition is in the range of about 1 :1 to about 1 :5.
9. The modified release solid oral pharmaceutical composition of claim 2, wherein the ratio of amount of cyclobenzaprine or a salt thereof and water soluble release modifying substances in the coating is in the range of about 10:1 to about 2:1 .
10. The modified release solid oral pharmaceutical composition of claim 3, wherein the ratio of amount of cyclobenzaprine or a salt thereof and water insoluble release modifying substances in the coating is in the range of about 10:1 to about 2:1 .
1 1 . The modified release solid oral pharmaceutical composition of claim 2, wherein the comprising:
(a) a core comprising cyclobenzaprine or salt thereof, hypromellose, lactose monohydrate and microcrystalline cellulose and magnesium stearate; and
(b) a coating comprising ethylcellulose-10 FP, polyvinyl pyrrolidone and triethyl citrate;
wherein the coating is devoid of water soluble substances.
12. The modified release solid oral pharmaceutical composition of claim 2, wherein the comprising:
(a) a core comprising cyclobenzaprine or salt thereof, hypromellose, lactose monohydrate, methacrylic acid copolymer and microcrystalline cellulose and magnesium stearate; and (b) a coating comprising hypromellose 5 cps, polyethylene glycol, talc and titanium dioxide to form a coated core,
wherein the coating is devoid of water insoluble substances.
13. A process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one release modifying substance and at least one pharmaceutically acceptable excipient with purified water to form granules;
(b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant;
(c) compressing the lubricated granules of step (b) to form a core, and
(d) coating the core of step (c) with one or more water soluble and/ or water insoluble release modifying substances.
14. A process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one release modifying substance and at least one pharmaceutically acceptable excipient with purified water to form granules;
(b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant;
(c) compressing the lubricated granules of step (b) to form a core, and
(d) coating the core of step (c) with one or more water soluble release modifying substances,
wherein the coating is devoid of water insoluble substances.
15. A process for preparation of a modified release solid oral pharmaceutical composition comprising steps of:
(a) granulating cyclobenzaprine or salt thereof, at least one release modifying substance and at least one pharmaceutically acceptable excipient with purified water to form granules; (b) lubricating the granules of step (a) with pharmaceutically acceptable lubricant;
(c) compressing the lubricated granules of step (b) to form a core, and
(d) coating the core of step (c) with one or more water insoluble release modifying substances,
wherein the coating is devoid of water soluble substances.
16. The modified release solid oral pharmaceutical composition of claim 1 , wherein the composition retains at least 90% w/w of the potency of cyclobenzaprine or a salt thereof when stored at 25°C and 40% relative humidity or at 40°C and 25% relative humidity for 3 months.
17. The modified release solid oral pharmaceutical composition of claim 1 , wherein the composition exhibits a release profile such that not more than about 40% of cyclobenzaprine or a salt thereof is released in 2 hours, not less than 40% of cyclobenzaprine or a salt thereof is released in 4 hours and not less than 60% of cyclobenzaprine or a salt thereof is released in 8 hours when measured in 900 imL of 0.1 N HCI at 37°C using USP Type II dissolution apparatus.
18. The modified release solid oral pharmaceutical composition of claim 1 , 2 or 3, wherein the composition provides therapeutically effective plasma concentration of cyclobenzaprine or a salt thereof over a period of 24 hours.
PCT/IB2015/051942 2014-03-29 2015-03-17 Modified release solid oral pharmaceutical compositions of cyclobenzaprine or a salt thereof WO2015150948A1 (en)

Applications Claiming Priority (8)

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IN1184/MUM/2014 2014-03-29
IN1185/MUM/2014 2014-03-29
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IN1186/MUM/2014 2014-03-29
IN1187MU2014 IN2014MU01187A (en) 2014-03-29 2015-03-17
IN1185MU2014 IN2014MU01185A (en) 2014-03-29 2015-03-17
IN1186MU2014 IN2014MU01186A (en) 2014-03-29 2015-03-17
IN1184MU2014 IN2014MU01184A (en) 2014-03-29 2015-03-17

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