WO2011086568A1 - Composition à libération contrôlée pour la lamotrigine - Google Patents

Composition à libération contrôlée pour la lamotrigine Download PDF

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Publication number
WO2011086568A1
WO2011086568A1 PCT/IN2010/000210 IN2010000210W WO2011086568A1 WO 2011086568 A1 WO2011086568 A1 WO 2011086568A1 IN 2010000210 W IN2010000210 W IN 2010000210W WO 2011086568 A1 WO2011086568 A1 WO 2011086568A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
core
pharmaceutical agent
coating
cellulose
Prior art date
Application number
PCT/IN2010/000210
Other languages
English (en)
Inventor
Santosh Shrikrishna Joshi
Kavita Vikram Inamdar
Abhijit Vishwanath Gothoskar
Smita Prashant Dhuri
Parag Manohar More
Original Assignee
Accutest Research Laboratories (I) Pvt. Ltd
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 Accutest Research Laboratories (I) Pvt. Ltd filed Critical Accutest Research Laboratories (I) Pvt. Ltd
Publication of WO2011086568A1 publication Critical patent/WO2011086568A1/fr

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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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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

  • This invention relates to a controlled release composition for the pharmaceutical agent.
  • the invention relates to a composition giving controlled release of pharmaceutical agent in two phases, it is also concerned with the materials and methods of preparing such compositions.
  • compositions are formulated in various dosage forms. For getting the desired effect of pharmaceutical agent with least adverse effects, its concentration maintenance within therapeutic window is very essential. Some pharmaceutical agents require their presence in the blood for long period to give desired
  • immediate release compositions in such cases need to be administered frequently to maintain the required level of pharmaceutical agent in blood.
  • controlled-release compositions can decrease the frequency of administration by making available the pharmaceutical agent for longer period with concentration falling within therapeutic window.
  • such compositions can reduce the large changes in blood concentration levels observed between consecutive immediate release doses.
  • Some pharmaceutical agents have the higher solubility in stomach than in the lower regions of the gastrointestinal tract. In such cases the controlled release compositions even if they give uniform release rate for pharmaceutical agent may lead to substantially linear increase in the blood concentrations of the pharmaceutical agent in vivo. There are some compositions which try to address this problem.
  • Lamicta!® XR sustained release tablet for sustained release composition gives the two phase release for lamotrigine, wherein the release in stomach is slower
  • the core of pharmaceutical agent is surrounded by a pH dependent coat which is substantially impermeable to the entrance of environmental fluid in core and to the exit of the pharmaceutical agent from core to environmental fluid.
  • This coating has one or more orifices extending from the outside of the coating substantially completely through said coating but not penetrating the inner core. These orifices have an area or combined area from about 10 to about 60 percent of the face area of composition. The release of pharmaceutical agent is controlled by these orifices.
  • This tablet provides the controlled release in two phases because the pH dependent coat remains intact in stomach and does not permit the release of pharmaceutical agent through it or in other words, limiting the release only through orifice whereas when the tablet reaches intestinal region, the coat get dissolved and release rate of pharmaceutical agent is higher than the release rate in stomach.
  • US6514531 describes controlled-release dosage of Zolpidem giving two phase release from an immediate release phase and from prolonged release phase. It showed the single capsule containing the prolonged release units and immediate release units which require separate preparation of these two units and then their incorporation in common capsule. It also showed the multilayer tablet containing distinct pharmaceutical agent containing layers of which one is immediate release layer and the second is a prolonged release layer. For preparing this tablet, the preparation of two separate layers, each containing pharmaceutical agent is necessary.
  • US6372255 disclosed multilayer tablet giving immediate release of pharmaceutical agent from first layer which is in contact with second layer made up of nonbiodegradable inert porous polymeric matrix which give prolonged release of pharmaceutical agent.
  • the invention describes a composition giving controlled release of pharmaceutical agent in two phases comprising a core containing a pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • the core containing a pharmaceutical agent in controlled release form comprises a core selected from a matrix core having release retarding polymers, a core formed by compacting together the plurality of pharmaceutical agent containing units giving slow release of pharmaceutical agent individually.
  • Such individual pharmaceutical agent containing units comprises granules, beads, spherules, mini-tablets, pharmaceutical agent coated particles, micro-capsules or combinations thereof.
  • the outer coating comprises a material which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • a material which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • Such material comprises alginates, gums, ionic synthetic or semi-synthetic polymers etc.
  • the invention describes method and materials for preparation of such composition.
  • the composition is prepared by first preparing the core and then applying on said core a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pK 5.
  • a core containing the pharmaceutical agent in controlled release form comprises matrix core having release retarding polymers therein.
  • Such matrix core is prepared by a method selected from direct compression method, dry granulation method or wet granulation method.
  • the release retarding polymer used in matrix core comprises the polymers bearing hydrophi!ic properties, hydrophobic properties, gelling properties, ionic nature, swelling property or combinations thereof.
  • a core containing the pharmaceutical agent in controlled release form is a core formed by compacting together the plurality of pharmaceutical agent containing units giving slow release of pharmaceutical agent individually.
  • Such pharmaceutical agent containing units comprise granules, beads, spherules, mini- tablets, pharmaceutical agent coated particles, micro-capsules or combinations thereof.
  • the methods for preparation of such pharmaceutical agent containing units comprises granulation method for preparing granules, spray coating onto non-pareil seeds for preparing beads, spheronization method for preparing spherules, fluid bed coating or granulation for preparing polymer coated pharmaceutical agent particles, microencapsulation methods for preparing micro-capsules.
  • the coating is applied on core by a method selected from compression coating, spray coating, fluid bed coating.
  • the coating comprises a material which forms gel upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. Such material is selected from alginates, gums, ionic synthetic or semi-synthetic polymers or combinations thereof.
  • the coating further comprises the material selected from film formers, diluents, lubricants, compression aid, surfactants, preservatives, p!asticizers, opacifying agents, coloring agents or any combinations thereof.
  • composition optionally comprises a seal coat between the core and the coating.
  • the invention specifically relates to a composition giving controlled release of pharmaceutical agent in two phases
  • a matrix core containing a pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • This matrix core comprises pharmaceutical agent, release retarding polymer, diluent and lubricant.
  • the amounts of pharmaceutical agent, release retarding polymer, diluent and lubricant suitable for incorporation in matrix core are from about 5 to about 75%, from about 5 to about 95%, from about 0 to about 90% and from about 0.05 to about 2% of the composition respectively.
  • the method for preparing matrix core comprises mixing above materials to form a blend followed by compressing this blended material to form core.
  • the coating comprises a material which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. More preferably, such material comprises sodium alginate.
  • the method for preparation of such composition comprises preparing a matrix core and applying on said core above mentioned coating. Preferably, such coating is applied with spray coating technique. More preferably, core is sprayed with coating comprising dispersion of sodium alginate in water.
  • Figures 1 , 2 and 3 shows the dissolution profile for Lamotrigine controlled release compositions giving controlled release in two phases, prepared according to examples 1 , 2 and 3 respectively.
  • a composition giving controlled release of a pharmaceutical agent in two phases comprises a core containing a pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • the controlled release of a pharmaceutical agent from the core is achieved by various means.
  • the non limiting examples for achieving controlled release of pharmaceutical agent from the core include forming matrix core having release retarding polymers therein, forming core by compacting together the plurality of pharmaceutical agent containing units giving slow release of pharmaceutical agent individually etc.
  • Individual pharmaceutical agent containing units mentioned above include without limitation, granules, beads, spherules, mini-tablets, pharmaceutical agent coated particles, micro-capsules or combinations thereof.
  • the core is surrounded with coating which forms gel structure upon contact with water or gastrointestinal fluid.
  • This gelation further controls the release of the pharmaceutical agent to outer environment. More particularly, the composition after oral administration reaches the stomach and due to contact with gastric fluid; the outer coating forms the gel structure due to presence of gel forming material in said coating. The penetration of gastric fluid through the said coating starts the first controlled release of pharmaceutical agent from the core. The released pharmaceutical agent from the core is slowly diffused from the gelled coating and reaches the outer environmental fluid.
  • the coating possesses leaky enteric property and it acts as further rate controlling unit after the core.
  • the coating material used herein dissolves and/or looses its integrity above pH 5.
  • the coating gets dissolved and/or looses its integrity when the composition reaches the intestine resulting in direct exposure of the core to the intestinal fluid.
  • the further release of pharmaceutical agent from remaining composition is attributable only to the core.
  • the release achieved only from the core is comparatively faster than the release from core and coating together.
  • the composition gives the two phase release of the pharmaceutical agent, first phase being in the stomach with slower release rate and second phase being in intestine with release rate higher than that of first phase.
  • the two phases release enable to achieve the desired non linear increase in blood concentrations of pharmaceutical agent for the defined period.
  • these pharmaceutical agents if delivered through the conventional controlled release compositions then there is a linear increase in the blood concentrations of pharmaceutical agents due to their throughout uniform release from the conventional controlled release composition.
  • the outer coating as mentioned above can be made from any material suitable for coating and which dissolves and/or looses its integrity at pH above 5. The non limiting examples of such material include alginates, gums, ionic synthetic or semisynthetic polymers etc.
  • the composition is prepared by first preparing the core containing a pharmaceutical agent in controlled release form and then applying on said core a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • the core containing a pharmaceutical agent in controlled release can be prepared by various means.
  • the non limiting examples for preparing a core giving controlled release of pharmaceutical agent include forming matrix core having release retarding polymers therein, forming core by compacting together the plurality of
  • the materials used with pharmaceutical agent for preparation of such core also vary according to type of core.
  • the examples of such materials include but not limited to release retarding polymers, bead materials, diluents, granulation aids, lubricants, binders, anti -adherents and compression aids or any combinations thereof.
  • release retarding polymers include but not limited to release retarding polymers, bead materials, diluents, granulation aids, lubricants, binders, anti -adherents and compression aids or any combinations thereof.
  • the particular choice of such material from the available variety at the time of core preparation should be based on suitability of such material with respect to pharmaceutical agent, type of core, compatibility and interaction of the said material with other materials of core and/or coating etc.
  • the release retarding polymers to be used in matrix core include without limitation, the polymers bearing hydrophilic properties, hydrophobic properties, gelling properties, ionic nature, swelling property or combinations thereof.
  • Polymers bearing hydrophobic properties include lipids, fatty acids, waxes and their chemical modifications etc.
  • the matrix core can be produced by direct compression method, dry granulation method or wet granulation method.
  • the various processes involved in these methods are sizing, blending, granulating, drying, compacting, lubricating etc.
  • the preparation methods for core containing plurality of individual units giving slow release of pharmaceutical agent as mentioned above vary according to the type of unit.
  • granules can be prepared by wet granulation using planetary or high shear granulation or in a fluid bed granulator by top spray or rotor granulation. Beads are usually prepared by bottom spray coating in fluid bed coater onto nonpareil seeds.
  • Spherules can be prepared by extrusion-spheronization or spheronization alone.
  • Mini tablets refer to tablets having diameters of 2 -3 mm or smaller which can be compressed into a single tablet. These can be prepared by conventional methods for preparing tablets using specific tablet tooling.
  • Pharmaceutical agent coated particles include pharmaceutical agent particles coated with polymer and are generally prepared by coating or granulating in a fluid bed coater or granulator respectively.
  • Micro-capsules refer to discrete particles of the active agent
  • Slow release pharmaceutical agent containing units can be prepared in any other way and using any other material based on their suitability to the current invention and without limiting to the materials and methods described above.
  • plurality of different types of individual units giving slow release of pharmaceutical agent can be compacted together to form the core.
  • plurality of slow release granules and slow release beads can be compacted together to form the core.
  • the coating can be applied to the core by various methods. For example,
  • Compression coating is applied on core by compressing the coating mixture on the core.
  • Spray coating is applied on core by spraying the dispersion of coating mixture on the core.
  • Such dispersion can be made by dispersing the coating mixture in a suitable solvent.
  • fluid bed coating the coating solution is sprayed onto a fluidized bed of tablets.
  • the coating mixture comprises a material which forms gel upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • the non limiting examples of such materials include alginates, gums, ionic synthetic or semi-synthetic polymers or combinations thereof.
  • the additional materials may be used in coating to facilitate the application of the coating on the core or to improve the physical properties of the coating or both.
  • the examples of such other materials include but not limited to film formers, diluents, lubricants, compression aid, surfactants, preservatives, plasticizers, opacifying agents, coloring agents or any combinations thereof.
  • the particular choice of such material from the available variety at the time of coating should be based on suitability of such material with respect to present invention. Such suitability factors for example include the compatibility and interaction of the said material with pharmaceutical agent and other materials of core or coating and may include the further assistance of such material in controlling the release rate of pharmaceutical agent from coating etc.
  • seal coat between the core and gel forming coating can be optionally introduced to maintain the integrity of the core.
  • the seal coat helps in maintaining the integrity of core especially if the core contains plurality of individual units giving slow release of pharmaceutical agent.
  • seal coat may be applied to make the core surface smooth so as to achieve easy and effective application of gel forming coating on it.
  • a composition giving controlled release of pharmaceutical agent in two phases comprises a matrix core containing the pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • composition preferably prepared by preparing matrix core comprising a pharmaceutical agent, release retarding polymer, diluent and lubricant.
  • amounts of pharmaceutical agent, release retarding polymer, diluent and lubricant suitable for incorporation in matrix core are from about 5 to about 75%, from about 5 to about 95%, from about 0 to about 90% and from about 0.05 to about 2% of the composition respectively.
  • These materials are mixed to form a blend and followed by compressing this blended material to form core using suitable punch.
  • Suitable release retarding polymer for use in above matrix core includes without any limitation, hydroxypropylmethyl cellulose, hydroxy propyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose, xanthan gum, carragenen, poly(ethy!ene oxide) polymers, carbomer, alginates, glyceryl - monostearate, glyceryl behenate, polyethylene glycol monostearate, triglycerides, carnauba wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid, beeswax, ion-exchange resins or any combination thereof.
  • Suitable diluent for use in above matrix core includes without limitation, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sorbitol, starch, pregelatinized starch, dicalcium phosphate or any combination thereof.
  • Suitable lubricant for use in above matrix core includes without limitation, magnesium stearate, talc, stearic acid, silicon dioxide, glycerly behenate, calcium stearate, sodium stearyl fumarate or any combination thereof.
  • the prepared core is applied with a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.
  • such coating is sprayed on core by preparing its dispersion in suitable solvent.
  • core is sprayed with coating comprising dispersion of sodium alginate in water.
  • said dispersion is coated to obtain from about 5 to 25 % weight gain of the core.
  • a seal coat can be applied on core prior to coating it with gel forming coating material as described above. It makes the core surface smoother and thus, it may facilitate the further application of gel forming coating.
  • the seal coat is applied on matrix core to obtain 0.5% to 5% weight gain.
  • Seal coat preferably comprises the material selected from cellulose ether polymers and polyvinyl alcohol-polyethylene glycol graft copolymer.
  • a seal coat of hydroxypropyl methyl cellulose is applied on the prepared cores to obtain 0.5 to 5 % weight gain.
  • the release in first 2 hrs shows the leaky enteric behaviour of sodium alginate coating. This coating started loosing its integrity in phosphate buffer as mentioned above.
  • the graphical representation for above dissolution profile is shown in figure 1. From the above data it is apparent that the release of lamotrigine in gastric similar environment was slower than in intestinal similar environment.
  • Hypromellose (viscocity: 3000 to 5600 cps) 21.50
  • a seal coat of hydroxypropyl methyl cellulose is applied on the prepared cores to obtain about 1.72 % weight gain.
  • a seal coat of hydroxypropyl methyl cellulose is applied on the prepared cores to obtain 1.72 % weight gain.
  • seal coat After applying seal coat, further coat these cores with sodium alginate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition à libération contrôlée pour agent pharmaceutique donnant une libération contrôlée de l'agent pharmaceutique en deux phases, la première phase dans l'estomac et la seconde phase dans les régions inférieures de l'appareil gastro-intestinal donnant une libération comparativement plus rapide (toujours contrôlée) que dans l'estomac. La composition comprend un cœur contenant un agent pharmaceutique à libération contrôlée, et un enrobage entourant ledit cœur qui forme une structure gélatineuse au contact de l'eau ou du fluide gastro-intestinal et qui se dissout et/ou perd son intégrité au dessus de pH 5. Elle apporte une libération contrôlée efficace jusqu'à un moment défini pour les agents pharmaceutiques ayant une solubilité supérieure dans l'estomac que dans les régions inférieures de l'appareil gastro-intestinal en les rendant disponibles in vivo pendant une période plus longue avec des concentrations se trouvant dans la fenêtre thérapeutique sans augmentation linéaire des concentrations sanguines, par opposition aux compositions à libération contrôlée classiques qui donnent une augmentation linéaire des concentrations sanguines en raison du taux de libération uniforme des agents pharmaceutiques.
PCT/IN2010/000210 2010-01-13 2010-03-31 Composition à libération contrôlée pour la lamotrigine WO2011086568A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN107/MUM/2010 2010-01-13
IN107MU2010 2010-01-13

Publications (1)

Publication Number Publication Date
WO2011086568A1 true WO2011086568A1 (fr) 2011-07-21

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PCT/IN2010/000210 WO2011086568A1 (fr) 2010-01-13 2010-03-31 Composition à libération contrôlée pour la lamotrigine

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004012741A1 (fr) * 2002-07-29 2004-02-12 Glaxo Group Limited Formulations a liberation prolongee contenant de la lamotrigine
EP2018851A1 (fr) * 2007-07-18 2009-01-28 Supernus Pharmaceuticals, Inc. Formulations de lamotrigine améliorées

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004012741A1 (fr) * 2002-07-29 2004-02-12 Glaxo Group Limited Formulations a liberation prolongee contenant de la lamotrigine
EP2018851A1 (fr) * 2007-07-18 2009-01-28 Supernus Pharmaceuticals, Inc. Formulations de lamotrigine améliorées

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