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EP2197424A2 - Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci - Google Patents

Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci

Info

Publication number
EP2197424A2
EP2197424A2 EP07819066A EP07819066A EP2197424A2 EP 2197424 A2 EP2197424 A2 EP 2197424A2 EP 07819066 A EP07819066 A EP 07819066A EP 07819066 A EP07819066 A EP 07819066A EP 2197424 A2 EP2197424 A2 EP 2197424A2
Authority
EP
European Patent Office
Prior art keywords
valaciclovir
pharmaceutical composition
calcium phosphate
dibasic calcium
phosphate dihydrate
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Withdrawn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
EP07819066A
Other languages
German (de)
English (en)
Inventor
Evangelos Karavas
Efthimios Koutris
Dimitrios Bikiaris
Vicky Samara
Anastasia Kalaskani
Eleni Stathaki
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.)
Pharmathen SA
Original Assignee
Pharmathen SA
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 Pharmathen SA filed Critical Pharmathen SA
Publication of EP2197424A2 publication Critical patent/EP2197424A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds

Definitions

  • the present invention relates to improved pharmaceutical formulations for oral administration and in particular to a pharmaceutical formulation for oral administration comprising a therapeutically effective quantity of an antiviral agent, and more particularly Valaciclovir or pharmaceutical acceptable salt or derivative thereof, in combination with an effective amount of Dibasic Calcium Phosphate Dihydrate and a method for the preparation thereof.
  • Acyclovir is a known compound widely used for the treatment of viral infections, particularly infections caused by the herpes virus. Pharmacokinetic studies have shown that acyclovir is poorly water soluble and presents poor oral bioavailability, therefore intravenous administration is required in order to achieve high concentrations in the plasma.
  • Valaciclovir or L-valyl acyclovir is a prodrug of acyclovir, and has been shown to posses antiviral properties and used for the treatment of the same types of infections as acyclovir.
  • Valacyclovir is the Valaciclovir hydrochloride salt. After oral administration, Valaciclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L -valine by first-pass intestinal and/or hepatic metabolism by enzymatic hydrolysis. It has been shown that Valaciclovir provides a high bioavailability of acyclovir, 3- to 5- fold higher than that obtained with oral acyclovir, and it is equivalent to plasma levels achieved with doses of intravenous acyclovir.
  • Valaciclovir tablets have been tried to increase the hardness and friability of Valaciclovir tablets by increasing the compression force, decreasing the proportion of lubricant and increasing the proportion of binder, but found in each case that a sufficiently hard and non-friable tablet could not be produced in a practical way.
  • Valaciclovir has adhesive properties in that it can stick to tablet dies and therefore needs to be efficiently lubricated.
  • elevated levels of hydrophobic lubricants can impact the mechanical strength of the tablets and disintegration/dissolution performance. It is difficult therefore to reduce the proportion of lubricant without causing the tablets to stick.
  • Valaciclovir tablet is also quite long and therefore any possible solution to the hardness and friability problem should not have a substantial deleterious effect on either the disintegration time or lubrication of the tablet.
  • the formulation of Valaciclovir granules was also found to be problematic due to the adhesive properties of Valaciclovir and also to problems relating to the pH dependent dissolution rate and discolouration of the granules. Granules of Valaciclovir itself tend to be fragile and have a low coating efficacy. Furthermore, there is a need to mask the bitter taste of Valaciclovir.
  • EP 0 806 943 discloses a pharmaceutical composition which comprises Valaciclovir within the granules and colloidal silicon dioxide and microcrystalline cellulose extragranularly.
  • EP 1 541 133 discloses a pharmaceutical formulation comprising Valaciclovir and titanium dioxide.
  • EP 1 278 515 is disclosed a composition comprising beads with a layer of Valaciclovir.
  • an object of the present invention to provide an improved solid dosage formulation for oral administration containing a high portion of an antiviral agent, and in particular Valaciclovir or pharmaceutical acceptable salts thereof as an active ingredient, which overcomes the deficiencies of the prior art.
  • It is another object of the present invention is to provide a solid dosage formulation for oral administration containing an antiviral agent, and in particular Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, which has a sufficient hardness and friability with satisfactory disintegration time, lubrication properties, flow properties and good pharmacotechnical properties.
  • a further aspect of the present invention is to provide a method for the preparation of a stable solid dosage formulation for oral administration containing a high portion of an antiviral agent, and in particular Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, thereby improving the friability, hardness, flow properties and the pharmacotechnical characteristics of the composition.
  • a pharmaceutical composition for oral administration comprising a high proportion of an antiviral agent or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, and an effective quantity of Dibasic Calcium Phosphate Dihydrate to improve friability, hardness and flow properties of the composition.
  • Dibasic Calcium Phosphate Dihydrate by mixing the remaining quantity of Dibasic Calcium Phosphate Dihydrate and at least one optional excipient such as a binder, disintegrant, lubricant, a colorant, and/or a glidant until uniform,
  • the term "pharmaceutically acceptable salt” refers to a salt that is not toxic at the specific therapeutic dosage and to a salt that does not independently possess significant pharmacological activity.
  • An excipient is considered to be "incompatible" with an active ingredient (an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) if it inhibits the dissolution rate of said active ingredient, that is to say, if said active ingredient (an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) dissolves less or slower in the presence of said excipient when compared with the dissolution rate of said active ingredient on its own.
  • an active ingredient an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof
  • the active ingredient (Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) contained in a dosage form is "bioavailable", if when administered in a dosage form is released from the dosage form, absorbed and reaches, at least the same, concentration levels in plasma as any of the marketed products containing the same quantity of the same active ingredient and intended for the same use.
  • the improved solid pharmaceutical composition of the present invention is characterized by physicochemical properties suitable for the tablet formulation by wet granulation, the adequate release rate of the active ingredient (an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) and the storage stability, by employing suitable pharmaceutically acceptable excipients.
  • the pharmacotechnical properties of pharmaceutical tablets include friability, hardness and flowability of the granules.
  • Tablet friability is defined as the percentage value of weight loss due to abrasion. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable.
  • Tablet hardness constitutes another important pharmacotechnical property during tablet manufacture. Tablet hardness is associated with several tablet properties, including density and porosity. Hardness generally increases with normal storage of tablets, and depends on the shape, chemical properties, binding agent, as well as pressure applied during compression. If a tablet is too hard, then it may not disintegrate in the required period of time to meet the dissolution specifications, hi contrast, if a tablet is too soft, then it may not be able to withstand the handling during subsequent processing, such as coating or packaging.
  • Flow property or fluidity is a characteristic required in order to produce tablets of a consistent weight and uniform strength. This means that good flowability is desirable for content uniformity and less weight variation in final tablets. In addition to that, compressibility is required to form a stable, intact compact mass when pressure is applied.
  • Pharmaceutical formulations with acceptable flow property and compressibility characteristics for granules can be obtained by incorporating suitable excipients. Flow property of tablet granules is defined via the known term "Carr's Compressibility Index".
  • dissolution rate of the drug from the primary particles of the tablet constitutes the important factor in drug absorption and for many formulations is the rate- limiting step. Therefore, the dissolution rate is an indication of the availability of the active ingredient from the tablet.
  • Dibasic Calcium Phosphate Dihydrate constitutes a diluent with excellent flowability and compressibility properties resolving the flow and hardness problems associated with high dose active ingredient formulations. It is practically insoluble in ethanol, ether, and water, and soluble in dilute acids. It is widely used in tablet formulations because of its compaction properties, and the good flow properties. It is also non hygroscopic and stable at room temperature. However, under certain conditions of temperature and humidity, it tends to lose water of crystallization below 100°C.
  • dibasic calcium phosphate dihydrate are used in the pharmaceutical industry.
  • the milled material is typically used in wet- granulated, roller-compacted or slugged formulations, whereas the 'unmilled' or coarse- grade material is typically used in direct-compression formulations.
  • Dibasic calcium phosphate is a white, odorless, tasteless crystalline powder. It is not consisted of individual crystals but aggregates of crystallites that undergo fragmentation caused by brittle fracture upon compaction and thus promoting inter-particulate interaction by creating numerous clean surfaces for bonding.
  • any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with the poor flow properties and unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability and the dissolution rate of the finished dosage form, and provide a product exhibiting excellent bioavailability.
  • sodium starch glycolate is incorporated into the composition of the present invention by internal addition (intragranular) and by external addition (extragranular).
  • the disintegrating agent is mixed with other powders prior to wetting the powder mixture with the granulating fluid.
  • the disintegrating agent is added to the granulate composition prior to compression.
  • the tablet can be disrupted into the previously compressed granules.
  • Sodium starch glycolate also presents the tendency to absorb water rapidly, so it swells in a significant amount. Therefore, this rapid water absorption by sodium starch glycolate molecules has as a result a significant increase in the volume of granules resulting to rapid and uniform disintegration
  • HPC Hydroxypropyl cellulose
  • the present invention can be applied in the formulation of tablets, capsules, caplets, sachets or other solid dosage forms for oral administration of an active ingredient having friability, hardness and flow properties problems.
  • the present invention provides a pharmaceutical composition comprising from about 40% to 90% by weight of Valaciclovir or salt thereof and from about 0.5% to 20% by weight of Dibasic Calcium Phosphate Dihydrate.
  • the weight ratio of Valaciclovir or salt thereof to Dibasic Calcium Phosphate Dihydrate is preferably 2:1 to 180:1.
  • More preferred pharmaceutical compositions according to the present invention comprise approximately 0.5% to 20%, more preferably 0.75% to 15% and most preferably 1% to 15% by weight of Dibasic Calcium Phosphate Dihydrate.
  • the preferred pharmaceutical compositions are in the form of solid dosage forms for oral administration such as tablets, capsules, caplets, troches, pastilles, pills, lozenges and the like, in all shapes and sizes, coated or uncoated.
  • the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.
  • Another embodiment of the present invention is the use of the wet granulation process for the preparation of solid dosage forms for oral administration such as tablets, capsules and sachets containing an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, which comprises:
  • a first homogenous blend by mixing the total quantity of said active ingredient with a portion of the total quantity of Dibasic Calcium Phosphate Dihydrate to improve friability, hardness and flow properties of the composition, and optionally at least a disintegrant such as Sodium Starch Glycolate, and the remaining portion of the binder; - Kneading the above mixture with the granulating solution; - Sieving the wetted mass through a sieve and forming granules
  • Dibasic Calcium Phosphate Dihydrate a second blend by mixing the remaining quantity of Dibasic Calcium Phosphate Dihydrate, and at least one optional excipient such as binder, surfactant, disintegrant, lubricant, colorant, and/or glidant until uniform,
  • the tablets are optionally coated by water soluble coating agents.
  • any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form composition.
  • Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, surfactants, wetting agents, glidants, lubricants, flavours, water scavengers, colorants, sweetener, coating agents and preservatives.
  • the optional excipients must be compatible with the selective estrogen receptor modulator or the salt thereof so that it does not interfere with it in the composition.
  • Diluents may be, for example, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose D dehydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol.
  • Binders may be, for example, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, and sucrose.
  • Disintegrants may be, for example, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, starch, pregelatinized starch.
  • Surfactants may be, for example, poloxamer, pluronic, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, as well as sodium docusate or sodium lauryl sulphate.
  • Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.
  • Lubricants may be e.g. magnesium stearate, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, talc.
  • the following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:
  • excipients are critical in order to fulfill the objects of the present invention.
  • those excipients should be compatible with the active ingredient.
  • Valaciclovir was tested for its compatibility with several pharmaceutically acceptable excipients comprising the above mentioned properties.
  • Example 1 Tablet of 500mg Valaciclovir (composition 1)
  • Tablets of the above formulation were prepared according to the following manufacturing process: Valaciclovir, a portion of the total quantity of HPC, a portion of the total quantity of Dibasic Calcium Phosphate Dihydrate as diluent and a portion of the total quantity of Sodium Starch Glycolate as a disintegrant were admixed to complete homogeneity.
  • the remaining quantity of HPC as a binder was dissolved in a mixture of ethanol and water and stirred for an adequate period of time till it was completely dissolved.
  • the first blend was kneaded with the granulating solution described above until it becomes homogenous. Sieving the resulting mixture through a sieve and forming the granules. Drying the granules and sieving.
  • the excipients of the external phase namely the remaining quantity of Dibasic Calcium Phosphate Dihydrate, the remaining quantity of Sodium Starch Glycolate, and the total amount of Talc and Mg stearate were added in the above formed granules and mixed.
  • Tablets prepared according to example 1 demonstrate good hardness (>80 Nt), very good friability (0.17%) and the granule has excellent flowability (Carr's index 11.8%).
  • the produced tablets were tested for content uniformity, disintegration, water content and dissolution proving that they are meeting the specifications.
  • Example 2 Tablet of 500mg Valaciclovir (composition 2)
  • Tablets of the composition 2 of Example 2 were prepared according to the manufacturing process used in Example 1.
  • dibasic calcium phosphate dihydrate has been replaced by dibasic calcium phosphate anhydrous.
  • Dibasic calcium phosphate anhydrous posses the same properties as the dihydrate, however when compacted at high pressures exhibits lamination and capping, especially when the material represents a substantial proportion of the formulation.
  • the tablets produced had low hardness (only up to 42Nt) and high friability (0.55%). In addition, capping problems were observed.
  • Composition 1 and Composition 2 were also tested for their stability for a three months period in normal (25°C ⁇ 2°C/60% ⁇ 5% RH) and accelerated (40°C ⁇ 2°C/75% ⁇ 5% RH) conditions. As it can be seen from Table 1 below the composition of example 1 is more stable compared to the one of example 2.
  • dibasic calcium phosphate dihydrate is consisted of aggregates of crystallites that undergo fragmentation caused by brittle fracture upon compaction and thus promoting inter-particulate interaction by creating numerous clean surfaces for bonding. Bonds may be created with the water distributed over the surface and/or distributed through the body and/or contained in the solid crystals of Valaciclovir hydrochloride hydrated forms and thus promoting stability and better pharmacotechnical properties.
  • TABLE 1 Stability results for Valaciclovir compositions of examples 1 and 2 in normal and accelerated conditions
  • Example 3 Tablet of 500mg Valaciclovir (composition 3)
  • Tablets of the composition 3 of Example 3 were prepared according to the manufacturing process used in Example 1.
  • composition 3 microcrystalline cellulose has been used as filler.
  • the tablets produced according to example 3 had lower hardness ( ⁇ 63Nt), higher friability (0.82%) and worse granule flow properties (Carr's index 21.6%) in comparison with example 1.
  • Example 4 Tablet of 500mg Valaciclovir (composition 4)
  • Tablets of the composition 4 of Example 4 were prepared according to the manufacturing process used in Example 1.
  • composition 4 a combination of dibasic calcium phosphate dihydrate with microcrystalline cellulose as diluents has been used.
  • the tablets produced according to example 4 had hardness ( ⁇ 75Nt), friability (0.33%) and granule flow properties (Carr's index 18.8%).
  • the pharmacotechnical properties for example 4 were better than example 3 but still worse than example 1.
  • Example 5 Tablet of 500mg Valaciclovir (composition 5)
  • composition 5 of Example 5 Tablets of the composition 5 of Example 5 were prepared according to the manufacturing process used in Example 1.
  • lactose monohydrate has been used as filler.
  • the tablets produced according to example 5 had the lower hardness ( ⁇ 42Nt), the higher friability (1.14%) and the worse granule flow properties (Carr's index 30.7%).
  • One of the most critical pharmacotechnical tests is the dissolution test as it is strongly correlated with the bioavailability of the product.
  • composition of example 1 meet the specifications of the product (>65% dissolved in 30 min and >85% dissolved in 60 min) for the dissolution test in a greater degree than the other two compositions.
  • composition of example 1 illustrated the best performance according to the objects of the present invention (hardness, friability, flow properties, dissolution rate). Tablets of this composition were prepared in larger scale and packed in PVC/PE/PVDC aluminum blisters and exposed to normal (25°C ⁇ 2°C/60% ⁇ 5% RH), intermediate (30°C ⁇ 2°C/65% ⁇ 5% RH) and accelerated (40°C ⁇ 2°C/75% ⁇ 5% RH) stability studies, according to the current ICH guidelines. The stability results after 6 months for accelerated conditions are shown in the table 3 below.
  • composition 1 described above was investigated for its scalability, while a process validation was performed in order to prove the repeatability and accuracy of the manufacturing process and the proposed formulation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique de formes de dosage solide comprenant une quantité thérapeutiquement efficace d'un agent antiviral, et en particulier le Valaciclovir ou un sel pharmaceutique acceptable ou un dérivé de celui-ci, en combinaison avec un diluant efficace, tel que le dihydrate de phosphate de calcium dibasique. La présente invention concerne également un procédé de préparation de celle-ci par granulation humide.
EP07819066A 2007-10-17 2007-10-17 Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci Withdrawn EP2197424A2 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/008998 WO2009049648A2 (fr) 2007-10-17 2007-10-17 Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci

Publications (1)

Publication Number Publication Date
EP2197424A2 true EP2197424A2 (fr) 2010-06-23

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EP07819066A Withdrawn EP2197424A2 (fr) 2007-10-17 2007-10-17 Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci

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EP (1) EP2197424A2 (fr)
WO (1) WO2009049648A2 (fr)

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EP2165706A1 (fr) 2008-09-18 2010-03-24 BioAlliance Pharma Traitement de la douleur inflammatoire de la muqueuse de la cavité buccale à l'aide de supports thérapeutiques bioadhésifs de muqueuse à libération prolongée
EP2335690A1 (fr) * 2009-12-09 2011-06-22 BioAlliance Pharma Comprimés buccaux mucoadhésifs pour le traitement de l'herpès orofacial
US8592434B2 (en) 2009-12-09 2013-11-26 Bioalliance Pharma Sa Mucoadhesive buccal tablets for the treatment of orofacial herpes
DK2509586T3 (en) * 2009-12-09 2018-08-06 Vectans Pharma MUCOADHASIVE BUCHALT TABLETS FOR THE TREATMENT OF OROFACIAL HERPES
SI3169311T1 (sl) * 2014-07-17 2023-12-29 Pharmathen S.A. Pediatrični prah za oralno suspenzijo, ki vsebuje protivirusno sredstvo in postopek za njegovo uporabo
DK3174521T3 (en) * 2014-07-31 2018-12-17 Pharmathen Sa PEDIATRIC CHEESE TABLE CONTAINING ANTIVIRAL AGENT AND METHOD OF PRODUCING THEREOF

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WO2001062229A1 (fr) * 2000-02-24 2001-08-30 Advanced Pharma, Inc. Produit therapeutique, son application et sa formulation
US7674480B2 (en) * 2000-06-23 2010-03-09 Teva Pharmaceutical Industries Ltd. Rapidly expanding composition for gastric retention and controlled release of therapeutic agents, and dosage forms including the composition
US6541014B2 (en) * 2000-10-13 2003-04-01 Advancis Pharmaceutical Corp. Antiviral product, use and formulation thereof
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Also Published As

Publication number Publication date
WO2009049648A3 (fr) 2009-10-01
WO2009049648A2 (fr) 2009-04-23

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