US20050269722A1 - Process for the preparation of pharmaceutical microcapsules with enhanced taste-masking and high dissolution rate - Google Patents

Process for the preparation of pharmaceutical microcapsules with enhanced taste-masking and high dissolution rate Download PDF

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US20050269722A1
US20050269722A1 US10/521,598 US52159805A US2005269722A1 US 20050269722 A1 US20050269722 A1 US 20050269722A1 US 52159805 A US52159805 A US 52159805A US 2005269722 A1 US2005269722 A1 US 2005269722A1
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drug
microcapsules
step
coating
process according
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Stefano De Luigi Brushci
Luigi Mapelli
Leonardo Rabaglia
Luigi Boltri
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Allergan Pharmaceuticals International Ltd
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Allergan Pharmaceuticals International Ltd
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Priority to PCT/EP2002/007961 priority Critical patent/WO2004009058A1/en
Assigned to EURAND PHARMACEUTICALS LTD. reassignment EURAND PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DE LUIGI BRUSCHI, STEFANO, MAPELLI, LUIGI GIOVANNI, RABAGLIA, LEONARDO
Publication of US20050269722A1 publication Critical patent/US20050269722A1/en
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02Making microcapsules or microballoons
    • B01J13/06Making microcapsules or microballoons by phase separation
    • B01J13/08Simple coacervation, i.e. addition of highly hydrophilic material
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5073Microcapsules 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
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02Making microcapsules or microballoons
    • B01J13/06Making microcapsules or microballoons by phase separation

Abstract

Process for the production of microcapsules containing a drug and comprising a layer of ethylcellulose and a layer of an acrylic polymer and microcapsules produced thereby.

Description

    FIELD OF THE INVENTION
  • 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.
  • The 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. in the order of 500 μm or less: to achieve this goal, the aggregation of the formed microcapsules must be avoided.
  • In the pharmaceutical field, 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. 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.
  • 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.
  • For the purpose of obtaining a good taste masking, 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. However ethylcellulose-coated microparticles are not capable to associate, to the good taste masking, an elevated dissolution rate in the stomach. In order to overcome this problem, 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 use of coating polymers alternative to ethylcellulose, having e.g. higher solubility in the stomach is equally unsatisfactory: in fact, these polymers require much a thicker coating to achieve the same level of taste masking of ethylcellulose; as a result microcapsules with very low potency are obtained: they require bulky dosage forms such as large tablets or capsules, thus quite problematic from the point of view of patient acceptability. In addition, with respect to ethylcellulose, polymers with higher solubility present problems of particle aggregation during the coating process, with the result that small-size singly coated microparticles are yet more difficult to obtain.
  • At present no microencapsulation process is available, capable to produce small microcapsules, ensuring at the same time a good taste masking, a fast onset of action, and a high potency.
  • SUMMARY OF THE INVENTION
  • 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.
  • DESCRIPTION OF THE FIGURES
  • FIG. 1: Caffeine, microscope image of lot. B1, described in the experimental part, showing an evident aggregation phenomena.
  • FIG. 2: Teophylline, particle size distribution of microcapsules of invention (lot. C2)
  • FIG. 3: Fluoxetine, microscope image of lot. C3, representing the microcapsules of the invention.
  • FIG. 4: Caffeine, microscope image of lot. C1, representing the microcapsules of the invention.
  • DETAILED DESCRIPTION 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.
  • The known process of 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. As a result, fluid droplets of coacervate coalesce and enwrap the drug cores with a continuous layer of membrane (gel phase). 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; (iii) hardening: the fluid polymeric film is hardened by cooling down the suspension to room temperature; (iv) 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 the fluidized bed coating. In this case the ethylcellulose coating can be ensured by spraying onto pharmaceutical cores either an organic solution or an aqueous dispersion of the polymer. The choice is strictly dependent on the chemical and physical characteristics of the cores to be coated.
  • If the next 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. Preferably 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).
  • To apply the additional coating of acrylic polymer (step b.), it is preferable to use a spray-coating technique: according to this embodiment, the microcapsules obtained in step a. are suspended in a fluidised bed and sprayed with a solution or suspension of the acrylic polymer. Preferably, the solvent used to form this solution or suspension is an acidic aqueous solvent, a hydroalcoholic solvent, an organic solvent, or mixtures thereof. When a hydroalcoholic solution is used, 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.
  • Advantageously, 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 HCl); 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 μm, preferably 100-400 μm, 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. containing lesser amounts of coating polymers) which are being more acceptable by the patient. 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.
  • Moreover the obtained 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.
  • The process and microcapsules of the invention can be used to taste-mask a wide variety of active ingredients that have a bitter or non-bitter taste and that are desired to be released rapidly. 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, psychostimulants, sedatives, antimigrane agents antituberculosis agents and tranquilizers. Generally, the actives used in conjunction with the present methodology are those which are bitter or otherwise unpleasant-tasting and thus in need of taste masking.
  • The present invention is now illustrated by reference to the following experimental examples which have no limiting function.
  • Experimental Part
  • Equipment
      • 5 L microencapsulation reactor
      • pneumatic stirrer/propeller
      • break-water
      • thermostat
      • Tray dryer
      • Fluid bed
        Materials
      • Caffeine
      • Teophyilline
      • Fluoxetine
      • Ethylcellulose
      • Polyethylene
      • Cyclohexane
      • Eudragit E
      • Micronised talc
      • Ethanol
      • Purified water
        Process Description
        Phase Separation
  • 3000 g of cyclohexane were poured into a 5 L 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 80° C. to cause the ethylcellulose solubilisation in cyclohexane.
  • The final microcapsules were dried in an oven overnight at 40° C. and sifted by 500 μm screen.
  • Fluid Bed Coating
  • 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:
    • Eudragit® E100
    • Micronised talc
    • Ethanol
    • Purified water
  • The second layer of coating suspension were subsequently applied. The final product was sifted by 500 μm 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.
  • Analytical Methods
  • Dissolution Rate Method (i):
  • USP Paddle, 900 mL or 500 mL, HCl 0.1N or pH 1.2 buffer, 50 or 100 rpm, 37° C. Samples were collected at fixed times, during, at least, 30 minutes time period. Data at 10 minutes and 30 minutes are reported.
  • Taste Masking Evaluation (TM)
  • Obtained by sensorial judgement.
  • A fixed amount of microcapsules was evaluated as is or after suspension in a appropriate aqueous media.
  • Particle Size Distribution (PSD)
  • Performed by sieve analysis using the automatic siever mod. Octagon Digital, equipped with sieves (Endecotts types).
  • D. Optical Microscopy (PSD)
  • Performed by a Ortolux microscope and a Zeiss Axioscopic 2 microscope.
  • Experimental Rationale
  • Three experimental sets were performed.
  • In the first set only the coating (i.e. ethylcellulose) was applied.
  • In the second set only the layer of the acrylic polymer was applied.
  • In the third set 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.
  • Results
    First Set
    Coating DRT DRT Potency
    Drug % w/w TM 10 min 30 min PSD % w/w Batch
    Caffeine 10 −− >80% >80% ++ 90 A1
    Caffeine 30 ++   30%   54% ++ 70 A2
    Theophylline 10 −− >80% >80% ++ 90 A3
    Theophylline 15 −−   57% >80% ++ 85 A4
    Theophylline 35 ++   19%   44% ++ 65 A5
    Fluoxetine 15 −− >80% >80% ++ 85 A6
    Fluoxetine 20 −− >80% >80% ++ 80 A7
    Fluoxetine 30 +−   37%   65% ++ 70 A8

    Legenda:

    PSD (Particle Size Distribution)

    ++: No significant aggregation

    −−: Significant aggregation

    +−: Improved but not acceptable

    TM (Taste Masking)

    ++: Satisfactory

    −−: Not satisfactory

    +−: Improved but not acceptable
  • From the evaluation of the aforementioned results, it's evident that:
      • at low level of coating the dissolution rate is quite fast, but the taste masking is not acceptable
      • at higher level of coating the taste masking properties significantly improve, but the release profile is too slow and therefore not acceptable. Moreover the potency decreases dramatically
      • in some cases, even using higher levels of coating (with a significant decrease of the dissolution rate), the taste masking is not acceptable. This is probably related to a higher surface area of the drug used.
  • the application of ethylcellulose, even at high percentage, leads to acceptable particle size distribution
    Second Set
    Coating DRT DRT Potency
    Drug % w/w TM 10 min 30 min PSD % w/w Batch
    Caffeine 10 −− n.a. n.a. −− 90 B1
    Theophylline 25 −− >80% >80% +− 75 B2
    Theophylline 40 −− >80% >80% +− 60 B3
    Fluoxetine 30 −− >80% >80% −− 70 B4
    Fluoxetine 40 −− >80% >80% −− 60 B5

    n.a.: not available. DRT was not performed due to dramatic agglomeration phenomena

    Legenda:

    PSD (Particle Size Distribution)

    ++: No significant aggregation

    −−: Significant aggregation

    +−: Improved but not acceptable

    TM (Taste Masking)

    ++: Satisfactory

    −−: Not satisfactory

    +−: Improved but not acceptable
  • From the evaluation of the aforementioned results, it's evident that:
      • the application of the acrylic polymer, even at high percentage, doesn't affect significantly the release in simulated gastric fluid, but is not able to assure the required taste masking
      • even applying a low level of acrylic polymer, the particle size distribution resulted not acceptable due to agglomeration phenomena.
  • In order to overcome this drawback, the coating of batches B2 and B3 was performed using a very low spraying rate, leading to a time consuming process, not economically compatible with an industrial application of this technology. Despite using this condition, the particle size distribution was not considered completely satisfactory due to a residual aggregation. Anyway the taste masking properties were not satisfactory.
    Third Set
    I Coating II Coating DRT DRT Potency
    Drug % w/w % w/w TM 10 min 30 min PSD % w/w Batch
    Caffeine 7.5 25 ++ >80%   >80% ++ 67.5 C1
    Theophylline 11.3 25 ++ 54% >80% ++ 63.7 C2
    Fluoxetine 24.2 15 ++ 76% >80% ++ 60.8 C3

    Legenda:

    PSD (Particle Size Distribution)

    ++: No significant aggregation

    −−: Significant aggregation

    +−: Improved but not acceptable

    TM (Taste Masking)

    ++: Satisfactory

    −−: Not satisfactory

    +−: Improved but not acceptable
  • From the evaluation of the aforementioned results, it's evident that:
      • The application of the two layers leads to microcapsules able to properly mask the taste, even when suspended in a liquid media, and also ensuring a fast release and avoiding significant microcapsule aggregation.
      • Moreover the overall coating amount is relatively low, so ensuring the possibility to obtain suitable potency.

Claims (14)

1. A process for the production of microcapsules containing a drug, comprising 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.
2. A process according to claim 1, where the coating in step a. is applied by phase separation microencapsulation or by fluidized bed coating.
3. A process according to claim 1, wherein the coating in step b. is applied by spraying a solution of suspension of acrylic polymer onto the particles obtained in a., suspended in a fluidized bed.
4. A process according to claim 3, wherein said solution or suspension is a hydroalcoholic solution, comprising the following weight percentages of components, calculated with respect to the total weight of the solution:
acrylic polymer: 4-20%
alcohol: 30-94%
water: 0-40%
micronised inorganic material: 2-20%
5. A process according to claim 3, wherein said hydroalcoholic solution or suspension comprises the following weight percentages of components, calculated with respect to the total weight of the solution:
acrylic polymer: 7-20%
alcohol: 40-75%
water: 10-35%
micronised inorganic material: 5-9%
6. A process according to claim 4, wherein said alcohol is ethanol, and said inorganic material is talc.
7. A process according to claim 1, wherein the product of step a. has a drug/ethylcellulose weight ratio (phase ratio) comprised between 1:1 and 30:1, and the product of step b. has an acrylic polymer content comprised between 5% and 40% by weight.
8. A process according to claim 1, wherein the product of step a. has a drug/ethylcellulose weight ratio (phase ratio) comprised between 3:1 and 15:1, and the product of step b. has an acrylic polymer content comprised between 10% and 25% by weight.
9. A process according to claim 1, wherein the taste-masked microcapsules obtained in step b. have a weight median diameter comprised between 20 and 800 μm, drug potency comprised between 400 and 950 mg/g, and are capable of releasing at least 80% of the drug contained therein within 30 minutes in a aqueous acidic media.
10. Microcapsules containing a drug, obtainable by the process described in claim 1.
11. Microcapsules according to claim 10, formulated in a pharmaceutical administrable form.
12. Microcapsules according to claim 11, wherein said pharmaceutical administrable form is chosen from dry powders for extemporaneous suspensions, tablets, minitablets, microcapsule-containing capsules, monodose sachets, fast disintegrating tables, syrups.
13. Microcapsules according to claim 10, wherein said drug is chosen from penicillins, cephalosporins, carbapenem, penems, penams, aminoglycosides, macrolides, ketolides, tetracyclines, quinolones.
14. A process according to claim 9 wherein the taste-masked microcapsules obtained in step b. have a weight median diameter comprised between 100 and 400 μM and a drug potency comprised between 400 and 950 mg/g.
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US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US8580313B2 (en) 2009-12-02 2013-11-12 Aptalis Pharma Limited Fexofenadine microcapsules and compositions containing them
US8747895B2 (en) 2004-09-13 2014-06-10 Aptalis Pharmatech, Inc. Orally disintegrating tablets of atomoxetine
US9040086B2 (en) 2001-10-04 2015-05-26 Aptalis Pharmatech, Inc. Timed, sustained release systems for propranolol
US9161919B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions

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US8357396B2 (en) 1996-06-14 2013-01-22 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8945618B2 (en) 1996-06-14 2015-02-03 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
US9040086B2 (en) 2001-10-04 2015-05-26 Aptalis Pharmatech, 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
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US10130580B2 (en) 2004-10-12 2018-11-20 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
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US9233105B2 (en) 2009-12-02 2016-01-12 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US8580313B2 (en) 2009-12-02 2013-11-12 Aptalis Pharma Limited Fexofenadine microcapsules and compositions containing them
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CA2492789C (en) 2012-07-03
AU2002368090A1 (en) 2004-02-09
JP2005537270A (en) 2005-12-08

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