EP1534251A1 - Procede pour la preparation de microcapsules pharmaceutiques avec masquage ameliore du gout et taux de dissolution eleve - Google Patents

Procede pour la preparation de microcapsules pharmaceutiques avec masquage ameliore du gout et taux de dissolution eleve

Info

Publication number
EP1534251A1
EP1534251A1 EP02807606A EP02807606A EP1534251A1 EP 1534251 A1 EP1534251 A1 EP 1534251A1 EP 02807606 A EP02807606 A EP 02807606A EP 02807606 A EP02807606 A EP 02807606A EP 1534251 A1 EP1534251 A1 EP 1534251A1
Authority
EP
European Patent Office
Prior art keywords
drug
microcapsules
coating
process according
acrylic polymer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02807606A
Other languages
German (de)
English (en)
Inventor
Stefano De Luigi Bruschi
Luigi Giovanni Mapelli
Leonardo Rabaglia
Luigi Boltri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Pharmaceuticals Holdings Ireland ULC
Original Assignee
Eurand Pharmaceuticals 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 Eurand Pharmaceuticals Ltd filed Critical Eurand Pharmaceuticals Ltd
Publication of EP1534251A1 publication Critical patent/EP1534251A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/08—Simple coacervation, i.e. addition of highly hydrophilic material
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation

Definitions

  • the present invention relates to the field of microencapsulation of active principles. A new process is described allowing to obtain pharmaceutical microcapsules with enhanced taste masking and an optimal dissolution profile. State of the art Achieving an effective encapsulation of active principles is important for the preparation of a variety of compositions; when microparticles of an active principle must be singly provided with an external coating, microencapsulation techniques are employed.
  • microencapsulation process consists in coating small drug cores (microparticles) with a layer of polymer.
  • the polymer layering may be achieved by different techniques; in particular the microencapsulation by phase separation (or coacervation), proved very reliable in obtaining coated microparticles (M.Calanchi, "Taste Masking of oral formulations", Pharmaceutical Manufacturing International, pp.139-141 , 1996; L. Dobetti, S. De Luigi, "Developments in Microencapsulation", Pharmaceutical Manufacturing and Packaging Sourcer, p. 39-40, Dec.1988).
  • the production of microcapsules differs from normal drug coating techniques in that singly coated, discrete microparticles must be obtained, e.g.
  • microencapsulation of active principles is applied in particular to prepare pharmaceutical multiparticulate compositions such as syrups, permanent or temporary suspensions, chewable or fast melting tablets, etc..
  • the microencapsulation is used in particular to mask the taste of those drugs characterised by bitterness, throat-burning, saltiness and localised numbing of the tongue, etc.
  • Microencapsulation is also used to modulate the drug release profile after administration. In principle, both taste masking and release-controlling properties are obtained by increasing the thickness of the microcapsule wall.
  • taste-masked, slow-release microcapsules As a consequence, it is easy to prepare taste-masked, slow-release microcapsules, whereas it is more difficult to obtain taste-masked quick-release ones: the latter form is nevertheless very desired, in particular for those drugs with unpleasant taste which, for pharmacokinetic and pharmacodynamic reasons, must be delivered quickly in the stomach: one typical example is that of antibiotic drugs (for example Penicillins, Cephalosporins, Carbapenem, Penems, Penams, Aminoglycosides, Macrolides, Ketolides, Tetracyclines, Quinolones, etc.) which are often endowed with an unacceptable taste: they require a strong taste- masking, but at the same time they must be delivered and absorbed quickly in the stomach, so to ensure a quick onset of action and avoid disturbing the intestinal bacterial flora.
  • antibiotic drugs for example Penicillins, Cephalosporins, Carbapenem, Penems, Penams, Aminoglycosides
  • a second example is that of antinflammatory drugs or drugs for pain relief. Often this kind of drugs needs to be taste masked to avoid bitterness or throat burning, but at the same time a fast absorption is mandatory to assure a fast pain relief.
  • Third example is that of drugs characterised by a narrow absorption window. These drugs require a fast release in the first part of the gastrointestinal tract to guarantee the proper bioavailability.
  • the preferred and most widely used sealing polymer is ethylcellulose.
  • This polymer is characterised by an efficient sealing capacity and is easily layered onto the drug microparticles; in addition it is an absolutely safe excipient, free from toxicity problems.
  • ethylcellulose-coated microparticles are not capable to associate, to the good taste masking, an elevated dissolution rate in the stomach.
  • attempts have been made to reduce the thickness of the microcapsule wall (i.e. using less encapsulating polymer); however this is not a good solution because the taste-masking is no longer ensured by the thinner coating.
  • the present application discloses a microencapsulation process characterised by coating drug cores with a first layer of ethylcellulose and further coating the obtained microcapsules with a layer of an acrylic polymer.
  • the obtained microcapsules show a high potency, an optimal taste masking, and ensure a quick release in the stomach.
  • the invention allows thus to produce superior pharmaceutical formulations, especially useful in the case of drugs with unpleasant taste in particular drugs, which require an immediate delivery in the stomach, even if the administration in form of reconstitutable suspensions is required.
  • Figure 1 Caffeine, microscope image of lot. B1 , described in the experimental part, showing an evident aggregation phenomena.
  • Figure 2 Teophylline, particle size distribution of microcapsules of invention (lot.
  • Figure 3 Fluoxetine, microscope image of lot.
  • C3 X representing the microcapsules of the invention.
  • Figure 4 Caffeine, microscope image of lot. C1 , representing the microcapsules of the invention.
  • a first objective of the present invention is a process for the production of microcapsules containing a drug, characterised by the following steps: a. - coating drug microparticles with a layer of ethylcellulose b. - further coating the product of a. with a layer of an acrylic polymer
  • the present process is particularly suitable for those drugs which have an unpleasant taste and require quick delivery into the stomach; however, any drug available in microparticular form can be subjected to the present process; for the purpose of the invention, the term "drug" includes also mixtures of two or more of them.
  • the step a. obtains singly coated microcapsules.
  • the coating step a. can be performed by microencapsulation techniques which, as such, are well-known in the art. Among them, microencapsulation by phase separation (also known as microencapsulation by coacervation ) is preferred.
  • phase separation can be summarised in the following, non limitative, step sequence: (i) dispersion: the creation of a two phase system in which a liquid phase (e.g. ethylcellulose solution in cyclohexane) and a solid phase (drug particles) are present simultaneously; (ii) phase separation: thanks to the action of the coacervation-inducing agent (e.g. an ethylene polymer like epolene) a third phase is formed.
  • This phase called coacervate is a highly concentrated polymer solution in solvent which spreads onto the surface of the suspended drug cores.
  • the deposition of the polymeric membrane is promoted by a reduction of the total free interfacial energy brought about by the decrease of the coating material surface area during the coalescence of the liquid droplets;
  • hardening the fluid polymeric film is hardened by cooling down the suspension to room temperature;
  • separation microcapsules are separated from the liquid medium by settling. The supernatant is then removed and the microcapsules can be washed with fresh solvent to remove the residues of phase separation agent. Finally the microcapsules are filtered, dried and sifted.
  • Another known technique applicable to perform step a is
  • step b. is also performed by fluidized bed coating, the overall process is particularly advantageous in that it can be performed in the same reactor by simply changing the coating solution when passing from step a. to b.
  • the product of step a. is an ethylcellulose microcapsule containing the drug.
  • the obtained microcapsule has a drug / ethylcellulose weight ratio comprised between 1 :1 and 30:1 , more preferably between 3:1 and 15:1.
  • the drug / ethylcellulose weight ratio is herein referred as PR (phase ratio).
  • PR phase ratio
  • the microcapsules obtained in step a. are suspended in a fluidised bed and sprayed with a solution or suspension of the acrylic polymer.
  • the solvent used to form this solution or suspension is an acidic aqueous solvent, a hydroalcoholic solvent, an organic solvent, or mixtures thereof.
  • a hydroalcoholic solution it preferably comprises the following weight percentages of components, calculated with respect to the total weight of the solution: acrylic polymer: 4-20%, preferably 7-20% alcohol (e.g. ethanol): 30-94%, preferably 40-75 water: 0-40%, preferably 10-35% micronised inorganic material (e.g. talc): 2-20%, preferably 5-9%.
  • the acrylic polymer can be layered indifferently during one or more layering steps: in the latter case a multilayered acrylic coating is obtained.
  • the product of step b. has an acrylic polymer content comprised between 5% and 40% by weight ; an optimal range of this polymer is 10-25%
  • the acrylic polymer used in step b. is chosen among acrylic polymers for pharmaceutical use: they are well-known in pharmaceutical technology, and can be indifferently linear, branched and/or cross-linked polymers of acrylic and/or methacrylic acid.; the chosen polymer must be soluble at acidic pH, (e.g. 1 g dissolves in 1N HCI); Representative, but not limitative examples of these polymers are the products of the class comprising Eudragit E (cationic copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic esters).
  • a further object of the present invention are the microcapsules obtained by the process above described.
  • the process according to the present invention allows to obtain small taste-masked microcapsules (i.e. having a weight median diameter comprised between 20 - 800 ⁇ m, preferably 100 - 400 ⁇ m, with potency (i.e. mg drug/g of the end product of step b.) comprised between 400 and 950 mg/g, and capable to release at least 80% of the drug contained therein within 30 minutes, preferably in 10 minutes in a simulated gastric fluid test or in acidic media.
  • the high level of potency is a pharmaceutically advantageous feature which allows to obtain, at constancy of drug content, smaller tablets or capsules, (i.e.
  • the reduction in the amounts of coating polymers involves the further advantage that the present compositions can dissolve in water without forming thickened viscous solutions around the drug cores: this further eases the drug diffusion and the establishing of a fast onset of action.
  • the obtained microcapsules further show the advantage of an improved suspendability in water, i.e. they do not form aggregates, do not float on the surface of a suspending medium, nor they adhere to side walls of a glass: therefore they do not require a separated wetting treatment with surfactants, such as instead required in case of ethylcellulose microcapsules.
  • microcapsules show the capability of maintaining the taste masking properties when suspended in neutral or basic aqueous media.
  • the use of resuspended dosage form is often required for easiness and effectiveness of administration (e.g. dosage form as monodose sachet and dry powders for extemporaneous suspension).
  • the above described microcapsules simultaneously ensuring elevated taste masking / elevated potency / elevated dissolution rate, are new and represent a further object of the present invention.
  • These microcapsules can be further processed, optionally in presence of suitable pharmaceutical excipients, into suitable pharmaceutical formulations, e.g. dry powders for extemporaneous suspensions, tablets, minitablets, microcapsule-containing capsules, monodose sachets, fast disintegrating tablets, syrups, etc.
  • Active ingredients useful with this invention include antibiotic and antibacterial agents such as ketolides; antiviral agents, analgesics, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti- inflammatory agents, antiemetics, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, H2 antagonists, cardiovascular drugs, antiarrhythmics, antihypertensives, ACE inhibitors, diuretics, vasodilators, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, psychostimul
  • Phase separation 3000 g of cyclohexane were poured into a 5L jacketed stainless steel reactor. Then, under a gentle stirring ensured by a helix, a fixed amount of drug, ethylcellulose and polyethylene were added.
  • the stirring rate was then increased to 500 rpm.
  • the system was then heated to
  • microcapsules were dried in an oven overnight at 40°C and sifted by 500 ⁇ m screen.
  • a fixed amount microcapsules obtained as described in the previous paragraph were loaded in a Glatt GPCG 1 fluid-bed equipped with 4" Wurster insert, plate type B, spraying nozzle 1.0 mm, and sprayed with a coating suspension having the following qualitative composition:
  • the second layer of coating suspension were subsequently applied.
  • the final product was sifted by 500 ⁇ m screen.
  • the coating level obtained was calculated as microcapsules theoretical weight gain.
  • Residual cyclohexane, residual ethanol and residual polyethylene were well within the acceptance limits for pharmaceuticals.
  • Particle Size Distribution Particle Size Distribution
  • the coating i.e. ethylcellulose
  • the drug microparticles were first coated with a layer of ethylcellulose and further with a layer of an acrylic polymer, according to what described in the present invention.
  • the overall coating amount is relatively low, so ensuring the possibility to obtain suitable potency.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dispersion Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention se rapporte à un procédé servant à produire des microcapsules contenant un médicament et comportant une couche d'éthylcellulose et une couche d'un polymère acrylique, ainsi qu'aux microcapsules ainsi produites.
EP02807606A 2002-07-17 2002-07-17 Procede pour la preparation de microcapsules pharmaceutiques avec masquage ameliore du gout et taux de dissolution eleve Withdrawn EP1534251A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2002/007961 WO2004009058A1 (fr) 2002-07-17 2002-07-17 Procede pour la preparation de microcapsules pharmaceutiques avec masquage ameliore du gout et taux de dissolution eleve

Publications (1)

Publication Number Publication Date
EP1534251A1 true EP1534251A1 (fr) 2005-06-01

Family

ID=30470213

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02807606A Withdrawn EP1534251A1 (fr) 2002-07-17 2002-07-17 Procede pour la preparation de microcapsules pharmaceutiques avec masquage ameliore du gout et taux de dissolution eleve

Country Status (6)

Country Link
US (1) US20050269722A1 (fr)
EP (1) EP1534251A1 (fr)
JP (1) JP4357422B2 (fr)
AU (1) AU2002368090A1 (fr)
CA (1) CA2492789C (fr)
WO (1) WO2004009058A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, Inc. Timed, sustained release systems for propranolol
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US8747895B2 (en) 2004-09-13 2014-06-10 Aptalis Pharmatech, Inc. Orally disintegrating tablets of atomoxetine
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
EP2417969A1 (fr) 2004-10-21 2012-02-15 Aptalis Pharmatech, Inc. Compositions pharmaceutiques à saveur masquée avec substances porogènes gastrosolubles
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US20070098746A1 (en) * 2005-11-02 2007-05-03 Nichols William M Multi-layered coating technology for taste masking
MX2012006240A (es) 2009-12-02 2012-10-03 Aptalis Pharma Ltd Microcapsulas de fexofenadina y composiciones que contienen las mismas.
CN103655483A (zh) * 2012-09-26 2014-03-26 扬州市星斗药业有限公司 一种含有替比培南的颗粒及其制备方法
EP2749273B1 (fr) * 2012-12-28 2021-04-07 I.P.S. International Products & Services S.r.l. Préparation solide orale à libération modifiée
EP3110403B1 (fr) 2014-02-25 2019-11-06 Orbis Biosciences, Inc. Préparations pharmaceutiques de masquage du goût
CN103893150B (zh) * 2014-03-28 2016-06-08 北京联合大学 一种青霉素v钾微囊及其制备方法

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DE4200821A1 (de) * 1992-01-15 1993-07-22 Bayer Ag Geschmacksmaskierte pharmazeutische mittel
US6197347B1 (en) * 1998-06-29 2001-03-06 Andrx Pharmaceuticals, Inc. Oral dosage for the controlled release of analgesic
JP2002530322A (ja) * 1998-11-25 2002-09-17 シーマ・ラブス・インコーポレイテッド 味隠蔽迅速放出コーティング系
FR2795962B1 (fr) * 1999-07-08 2003-05-09 Prographarm Laboratoires Procede de fabrication de granules enrobes a gout masque et liberation immediate du principe actif
US6419956B1 (en) * 1999-12-30 2002-07-16 Ancile Pharmaceuticals Odor-masking coating for a pharmaceutical preparation
US6451345B1 (en) * 2000-01-20 2002-09-17 Eurand Pharmaceuticals Ltd. Functional coating of linezolid microcapsules for taste-masking and associated formulation for oral administration

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Also Published As

Publication number Publication date
JP4357422B2 (ja) 2009-11-04
AU2002368090A1 (en) 2004-02-09
CA2492789C (fr) 2012-07-03
US20050269722A1 (en) 2005-12-08
WO2004009058A1 (fr) 2004-01-29
CA2492789A1 (fr) 2004-01-29
JP2005537270A (ja) 2005-12-08

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