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WO2007090595A1 - Formulations solides de chlorhydrate de valacyclovir - Google Patents

Formulations solides de chlorhydrate de valacyclovir Download PDF

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Publication number
WO2007090595A1
WO2007090595A1 PCT/EP2007/000966 EP2007000966W WO2007090595A1 WO 2007090595 A1 WO2007090595 A1 WO 2007090595A1 EP 2007000966 W EP2007000966 W EP 2007000966W WO 2007090595 A1 WO2007090595 A1 WO 2007090595A1
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WO
WIPO (PCT)
Prior art keywords
tablet
valacyclovir
methylcellulose
valacyclovir hydrochloride
starch
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Ceased
Application number
PCT/EP2007/000966
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English (en)
Inventor
Giorgio Reiner
Alberto Reiner
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FIDIA PHARMACEUTICI SpA
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FIDIA PHARMACEUTICI SpA
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Publication of WO2007090595A1 publication Critical patent/WO2007090595A1/fr
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Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to pharmaceutical formulations, and particularly to solid formulations of valacyclovir hydrochloride, such as tablets and granulates, and to methods of making and using such tablets and granulates.
  • Valacyclovir hydrochloride is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.
  • valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against herpes simplex virus types 1 (HSV-I) and 2 (HS V-2) and varicella-zoster virus (VZV).
  • HSV-I herpes simplex virus types 1
  • HS V-2 herpes simplex virus
  • VZV varicella-zoster virus
  • the drug is indicated for the treatment of herpes zoster (shingles), genital herpes, and cold sores (herpes labialis).
  • Valacyclovir hydrochloride is marketed as Valtrex ® in the United States, and Zelitrex ® in some countries outside the United States, by GlaxoSmithKline in 500 mg. and 1,000 mg. strength caplets for oral administration.
  • Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir, and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.
  • the blue, film- coated tablets are printed with edible white ink.
  • the drug is challenging from a formulation standpoint, especially when tablets are desired, because of the large amount of active drug ingredient required for antiviral activity and the low bioavailability of the active ingredient.
  • Commercial tablets are formulated to contain 500 mg. and 1,000 mg. of valacyclovir, which translates into more than 1,100 mg. of valacyclovir hydrochloride. When combined with other inactive excipients, the resulting weight of a 1,000 mg. Valtrex ® tablet is 1 ,425 mg.
  • Valacyclovir and its salts including the hydrochloride salt are disclosed in U.S. Patent No. 4,957,924, its counterpart European Patent No. 0308065 and Beauchamp et al, Antiviral Chemistry and Chemotherapy, 3(3), 157 - 164 (1992). Tablets of valacyclovir are also generally disclosed in the U.S. Patent No. 4,957,924 and its counterpart European Patent No. 0308065.
  • U.S. Patent No. 5,879,706 (corresponding to EP 0806943 Bl), is owned by GlaxoSmithKline and discloses a tablet formulation of valacyclovir in which valacyclovir is granulated along with microcrystalline cellulose, crospovidone, and povidone, and the granulates are mixed with microcrystalline cellulose, crospovidone and silicon dioxide before being compressed into tablets.
  • the alleged point of novelty in this patent is the use of silicon dioxide as an extra-granular excipient.
  • WO 2004/000265 is a PCT publication by Ranbaxy Laboratories that also discloses a tablet formulation of valacyclovir hydrochloride.
  • the formulation replaces the silicon dioxide in the extra-granulate disclosed in the U.S. '706 patent with hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and magnesium stearate.
  • U.S. Patent No. 6,117,453 (corresponding to EP 0830129 Bl) is a United States patent owned by Pharma Pass, that also discloses a tablet formulation of valacyclovir hydrochloride.
  • Granulates are prepared from valacyclovir and polyethylene oxide, and the granulates are mixed with excipients such as silicon dioxide, hydroxypropyl methyl cellulose and lactose before being compressed into tablets.
  • U.S. Patent No. 6,117,857 (corresponding to EP 0810865 Al) is owned by Astra Aktiebolag and discloses an antiviral topical or parenteral composition that includes valacyclovir hydrochloride in admixture with galactolipids and a polar solvent.
  • European Patent No. 1146862 Bl (no corresponding granted U.S. patent) is owned by Disphar International and discloses a controlled release formulation that lists valacyclovir among the drugs suitable for use with the formulation.
  • WO 03/022209 is owned by Teva Pharmaceutical, and discloses various polymorphs and pseudopolymorphs of valacyclovir, including valacyclovir hydrochloride monohydrate and valacyclovir hydrochloride dehydrate.
  • European Patent No. 1541133 Bl (no corresponding granted U.S. patent) is a granted European patent owned by Helm AG that discloses the use of titanium dioxide in the production of valacyclovir hydrochloride tablets.
  • the patent discloses a process in which valacyclovir, starch and lactose are mixed, added to a solution of povidone in alcohol, granulated, and mixed with magnesium stearate and titanium dioxide before compression into a tablet.
  • the patent teaches the desirability of using titanium dioxide in valacyclovir tablets to improve the density, compressibility and flowability of powders used to form the tablets.
  • the patent also teaches that at least 1% povidone, based on the total weight of the formulation, should be used to bind the granulate together and improve tablet hardness.
  • the total weight of a 1 ,000 mg. valacyclovir hydrochloride tablet using the preferred formulation disclosed in EP 1541133 would equal 1400 mg, which could be reduced somewhat to improve swallowability. What is needed is a formulation for valacyclovir that permits large amounts of valacyclovir to be incorporated into the dosage form, and still give excellent physical performance.
  • valacyclovir that are suitable for the production of tablets and granulates, especially valacyclovir hydrochloride tablets and granulates, and especially tablets and granulates that contain large proportions of valacyclovir hydrochloride.
  • Still another object of the present invention is to provide methods and formulations for processing valacyclovir into tablets that meet demanding disintegration, dissolution, and bioavailability requirements.
  • Solid oral dosage forms of valacyclovir particularly tablets of valacyclovir hydrochloride, have been developed using wet granulation techniques that (i) are stable over time, (ii) meet demanding physical handling requirements, (iii) have optimal bioavailability, and (iv) allow for the integration of large proportions of valacyclovir hydrochloride into the total formulation.
  • starch has intragranulate binding properties, and that valacyclovir hydrochloride can be manufactured into granulates using methylcellulose and starch in the granulate, based on a hydro-alcoholic granulation process.
  • Granulates based on the formulation can contain greater than even 90 wt.% of the active ingredient, while finished tablets can contain greater than even 85 wt.% valacyclovir hydrochloride.
  • the weight ratio of valacyclovir hydrochloride to methylcellulose is greater than 100:1 (giving rise to a formulation that contains less than 1 wt.% methylcellulose in the granulate and final formulation).
  • the granulate is substantially devoid of any fillers or binders other than starch and methylcellulose.
  • the invention provides a method of making a valacyclovir tablet comprising (a) wet granulating a mixture of valacyclovir hydrochloride, starch and methylcellulose to form a granulate; (b) mixing said granulate with a pharmaceutically acceptable excipient to form a blend; and (c) compressing said blend into a tablet.
  • the method is carried out by dissolving the methylcellulose in a hydro-alcoholic solution that comprises at least 50% water, and wet granulating the solution with valacyclovir hydrochloride and starch to form a granulate.
  • the granulate may subsequently be mixed with one or more binders and other pharmaceutical excipients and compressed into tablets.
  • the invention provides a valacyclovir tablet comprising an intragranular portion and an extragranular portion, wherein: (a) said intragranular portion comprises valacyclovir hydrochloride, starch and methylcellulose; and (b) said extragranular portion comprises one or more binding agents.
  • the invention provides a granulate comprising valacyclovir hydrochloride, starch and methylcellulose. In each of the foregoing embodiments, the granulate preferably comprises less 1 wt.% methylcellulose or greater than 82 wt.% valacyclovir hydrochloride.
  • FIG. 1 depicts a plot of percent dissolution over time for test Formula IV made according to the invention, where the solution pH 1.2 at time zero.
  • FIG. 2 depicts a plot of dissolution over time for Film Coated tablets (1000 mg valacyclovir) Batch VALA 111/60 made according to the invention versus 1000 mg Zelitrex tablets.
  • FIG. 3 depicts a plot of dissolution over time for Film Coated tablets (500 mg valacyclovir) Batch VALA 111/62 made according to the invention versus 500 mg Zelitrex tablets.
  • FIG. 4 depicts the DSC curve of a mechanical mixture of all components present in the dosage form in 1 : 1 ratio, as made according to the invention.
  • FIG. 5 depicts the DSC curve of a mechanical mixture of all the components in proportions close to Formula IV, as made according to the invention.
  • FIG. 6 depicts the DSC curve of a mechanical mixture of all the components present in the dosage form, as made according to the invention.
  • FIG. 7 depicts the DSC curve for a mechanical mixture with all the components present in the dosage form, as made according to the invention.
  • FIG. 8 depicts the DSC curve for a VALA III /44 tablet (final formulation before film coating) made according to the invention.
  • FIG. 9 depicts the comparative acyclovir plasmatic concentrations for tablets of type Tl (1000 mg) and T2 (2x500 mg) made according to the invention, and the corresponding plasmatic concentrations for references Rl (1000 mg Valtrex ® tablets) and R2 (1000 mg Zelitrex ® tablets).
  • FIG. 10 depicts the mean and range of acyclovir plasmatic concentrations over time on linear and logarithmic scales for tablets of type Tl (1000 mg valacyclovir) made according to the invention.
  • FIG. 1 1 depicts the mean and range of acyclovir plasmatic concentrations over time on linear and logarithmic scales for tablets of type Tl (2x500 mg valacyclovir) made according to the invention.
  • FIG. 12 depicts the mean and range of acyclovir plasmatic concentrations over time on linear and logarithmic scales for tablets of type Rl (Valtrex ® 1000 mg valacyclovir).
  • FIG. 13 depicts the mean and range of acyclovir plasmatic concentrations over time on linear and logarithmic scales for tablets of type Rl (Zelitrex ® 1000 mg valacyclovir).
  • a pharmaceutical excipient may refer to one or more pharmaceutical excipients for use in the presently disclosed formulations and methods.
  • Valacyclovir hydrochloride is a white to off-white powder with the molecular formula Ci 3 H 20 N 6 O 4 * HCI and a molecular weight of 360.80.
  • the chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-l,6-dihydro-6- oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:
  • Valacyclovir hydrochloride for use in this invention can exist in any crystalline form that the molecule is known to assume.
  • the term "valacyclovir hydrochloride” thus includes anhydrous forms, hydrates (e.g. the monohydrate, the sesquihydrate, or the dehydrate), solvates, and all crystalline forms (both polymorphs and pseudopolymorphs) of valacyclovir hydrochloride. Suitable forms are disclosed, for example, in U.S. Patent Nos. 4,957,924 and 6,107,302 of GlaxoSmithKline and WO 03/022209 of Teva Pharmaceuticals.
  • a preferred form of valacyclovir hydrochloride contains water of hydration in an amount of from about 3 to about 9 wt.%.
  • the pharmaceutical formulation of the present invention may comprise any suitable amount of the active ingredient.
  • the finished formulation preferably contains a high proportion of valacyclovir, such as at least 50 wt.%, and most preferably contains at least 75%, 80%, 82% or 85 wt.% valacyclovir hydrochloride based on the total weight of the formulation.
  • the granulates of the present invention preferably contain at least 75%, 80%, 85% or 90 wt.% valacyclovir hydrochloride.
  • the pharmaceutical formulation of the present invention is a solid, preferably oral composition, such as a tablet, capsule, granule, pellet or sachet, with the tablet dosage form being most preferred.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the water content of the formulation is preferably less than about 8, 7 or 6 wt.% and greater than about 3 or 4 wt.%.
  • Other preferred physical properties for tablet dosage forms are as follows, based on testing methods described in greater detail in Example 2:
  • Hardness greater than 235 or 250 N and less than 320, 300, 280 or 260 N
  • Friability greater than 0.00, 0.01 or 0.03% and less than 0.15 or 0.10%
  • Disintegration Time greater than 12, 15, 16 or 17 minutes and less than 25, 20 or 19 minutes as tested by USP 28 ⁇ 701>.
  • the tablets preferably exhibit a dissolution profile substantially as shown in Figure 1 hereto, when tested according to USP 28 ⁇ 711>.
  • compositions are preferably prepared first by granulating valacyclovir along with starch and methylcellulose in a series of steps.
  • the starch can constitute any commercially available grade of starch, including native starch, pregelatinized starch or a modified starch.
  • the granulate is preferably prepared by (a) mixing valacyclovir and starch to form a blend, (b) dissolving or suspending methylcellulose in a liquid to form a methylcellulose solution or suspension, (c) mixing the blend with the methylcellulose solution or suspension to form a wet suspension or liquid slurry, and (d) drying the wet suspension or liquid slurry to form a granulate.
  • the liquid is preferably a "hydro-alcohol" that contains at least 50 wt.% water, and more preferably comprises greater than 80 wt.% water, the balance preferably constituting ethanol.
  • the weight ratio of the valacyclovir hydrochloride to the methylcellulose in the granulate and/or finished tablet is greater than 100: 1, 250: 1 or even 500: 1, and less than about 5,000:1 or 2,000:1.
  • the weight ratio of the valacyclovir hydrochloride to the starch in the granulate and/or finished tablet is preferably greater than about 5: 1, 8:1 or even 10:1, and less than about 100:1 or 30:1.
  • the weight ratio of starch to methylcellulose in the granulate and/or finished tablet is preferably from about 40: 1 to about 100: 1, and more preferably from about 50:1 to about 80: 1.
  • the total weight of methylcellulose in the granulate or final formulation is preferably less than about 1.0%, 0.05%, or even 0.02% based on the weight of the granulate or formulation.
  • the total weight of starch is preferably less than about 20%, 15% or 10%, based on the total weight of the granulate or final formulation.
  • the granulate is preferably mixed with one or more pharmaceutically acceptable excipients (i.e. extragranular excipients) such as fillers, binding agents, lubricants and disintegrating agents, depending on the final dosage form and the properties desired.
  • excipients i.e. extragranular excipients
  • the weight ratio of the intragranular component to the extragranular component is from about 1 :5 to about 1 :30,and more preferably is from about 1 : 10 to about 1 : 15.
  • the intragranula ⁇ extragranular weight ratio is preferably greater than about 5: 1, 10: 1 or even 12: 1.
  • the extragranular portion preferably constitutes less than 15, 10 or even 8 wt.% of the total weight, whereas the intragranular portion preferably constitutes greater than 85, 90 or even 92 wt.% of the total weight.
  • filler materials for the extragranulate are well-known to the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990), Mack Publishing Co., Easton, Pa., pp. 1635-1636), and include lactose and other carbohydrates, pregelatinized starch, e.g., starch 1500® (Colorcon Corp.), corn starch, dicalcium phosphate, cellulose, microcrystalline cellulose, sugars, sodium chloride, and mixtures thereof. Owing to its superior disintegration and compression properties, microcrystalline cellulose (Avicel®, FMC Corp., or Vivapur Type 12), and mixtures comprising microcrystalline cellulose and one or more additional fillers, e.g., corn starch, are particularly useful.
  • the amount of the fillers present in the pharmaceutical formulation is not particularly limited and can be, for example, in the range of 0 to 30 wt.%, preferably 0.5 to 5 wt.% of the total weight of the formulation.
  • An extragranular binding agent e.g., gelatin, sugars, natural and synthetic gums, such as carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose
  • the binding agent is present in an amount of 0.01 to 5 wt.%, more preferably at 0.1 to 2 wt.% of the total weight of the formulation.
  • the extragranular binding agent can for example be methylcellulose or more preferably povidone or crospovidone.
  • the total amount of binding agent in the formulation, excluding starch is preferably less than about 10, 5, 2 or even 1 wt.%.
  • a lubricant is suitably present in an amount of 0.1 to 10 wt.%, preferably from about 0.5 to about 5 wt.% of the total weight of the formulation.
  • lubricants such as talc or sodium lauryl sulfate are suitable, as are alkali metal stearates such as magnesium stearate, in a preferred embodiment the lubricant is glyceryl behenate.
  • valacyclovir is very soluble, especially in its salt form, it is preferable if an extragranular disintegrating agent is present in the pharmaceutical formulation, suitably in an amount of 0.1 to 20 wt.%, more preferably at about 1.0 to 10 wt.% of the total weight of the formulation.
  • crosscarmellose sodium may be used as disintegrating agent or any other suitable disintegrating agent known to the person skilled in the art.
  • suitable disintegrants include, for example, cross-linked carboxymethylcellulose, crospovidone, and sodium starch glycolate.
  • formulations of the present invention do not require the presence of processing aids such as silicon dioxide or titanium dioxide, and in a preferred embodiment the formulations omit such processing aids.
  • ⁇ Tabletting machine alternated tabletting machine (A6) Preparation of the Mixture for Granulation Sieve all the ingredients, necessary for the preparation of the uncoated tablets, through a 1.40 mm sieve.(A5) Then weigh (Al) Valacyclovir HCl, Starch, mix in (A2) for 15 minutes. Add a solution composed with Methylcellulose (if any), Purified water, Ethanol under stirrer for 20 minutes. Unload the wet granulated on the tray of a static oven.
  • A6 Preparation of the Mixture for Granulation Sieve all the ingredients, necessary for the preparation of the uncoated tablets, through a 1.40 mm sieve.(A5) Then weigh (Al) Valacyclovir HCl, Starch, mix in (A2) for 15 minutes. Add a solution composed with Methylcellulose (if any), Purified water, Ethanol under stirrer for 20 minutes. Unload the wet granulated on the tray of a static oven.
  • Compress (A6) the mixture using oblong punches with these dimensions: Length 19, Width 9 mm. Collect the finished uncoated tablets in brown coloured glass container. Store at room temperature.
  • Valacyclovir HCl 1 12.0 mg 1 112.0 mg 1 1 12.0 mg 1 1 12.0 mg 1 1 12.0 mg 1 1 12.0 mg
  • Crospovidone (binder) 6.0 mg 6.0 mg 6.0 mg 6.0 mg 6.0 mg 6.0 mg 6.0 mg 6.0 mg
  • Methylcellulose (binder) 0 0 0.75 mg 1.5 mg 3 mg
  • Friability (according 0,33 % na 0,07 % 0,08 % 0,08 % Eur. Ph)
  • Disintegration time (37 0 C 2 min l4 sec. na 2 min 23 sec 18 min 29 min water) (Eur. Ph.) a -- Tablet not tested due to capping during tableting process and low hardness (40-60 N).
  • Hardness is determined on 10 finished product taken at random from different blisters, according to Eur. Ph.
  • the instrument used to measure hardness for the finished product is Erweka TBH 30 HD.
  • the instrument measures the force required to break the tablet when the force generated by a coil spring is applied diametrically to the tablet. The force is measured in Newtons (N).
  • Disintegration is measured in water (37 0 C) on 6 finished product taken at random from different blisters, according to Eur. Ph.. The disintegration time must be not more than 30 minutes.
  • EXAMPLE 3 MANUFACTURING PROCESS FOR 500 MG. AND 1000 MG. COATED AND UNCOATED TABLETS
  • Tabletting machine Ronchi ARl 8/23 rotating single layer tabletting press, equipped with 4 punches (23 mm x 9.5 mm)
  • film-coating film coating equipment GS Pellegnini (A7) Operating Procedures
  • the equipment and the premises are of type suitable for pharmaceutical preparations and are air-conditioned at 25°C to 28 0 C with 60% approximately relative humidity.
  • Compress (A6) the mixture using oblong punches with these dimensions: Length 23 mm, Width 9,5 mm.
  • Air inlet temperature Between 70.0°C and 75.O 0 C
  • Process time About 1 hour (drying included).
  • Batch VALA 111/62 and Batch VALA 111/46 500 mg. coated and uncoated tablets were prepared substantially as described for Batches VALA 111/44 and VALA 111/60, except that a smaller tablet punch was employed.
  • Dissolution testing of formulation IV, VaIa 111/60, VaIa 111/62, Zelitrex 500 and Zelitrex 100 were performed as described below and as set forth in USP 25 ⁇ 711>. Dissolution profile results are depicted in Figures 1, 2 and 3. Dissolution conditions
  • the dissolution test is performed by an Erweka DT800. Spectrophotom eter
  • Valacyclovir HCL weigh accurately about 60 mg of Valacyclovir HCL into a 100 ml volumetric flask. Dissolve with dissolution medium and sonicate for 5 minutes. Make up to volume. Transfer 1.0 ml of this solution into a 10 ml volumetric flask. Make up to volume with dissolution medium.
  • Valacyclovir HCl Compatability between Valacyclovir HCl, excipients and film coating components were investigated by differential scanning calorimetry to assess the compatibility among drug substance and excipients. Thermal events were recorded for each component and for various mixtures of components, and analyses were carried out comparing peaks recorded by DSC for various mixtures to individual peaks observed for valacyclovir HCl and the excipients under investigation.
  • Dry solids Aliquots of Valacyclovir HCl and excipient under investigation were weighed in a ratio of 1 : 1 or in the method ratio and ground in an agate mortar. Homogeneous powder was used for the analysis.
  • Figure 4 depicts the DSC curve of a mechanical mixture of all components present in the dosage form in 1 : 1 ratio.
  • a peak for the gliceril benehate can be observed at 70°C
  • a reduced peak for the valacyclovir hydrochloride is observed at 195 0 C
  • one other peak corresponding to the sodium lauryl sulphate is observed at 23O 0 C.
  • Figure 5 depicts the DSC curve of a mechanical mixture of all the components in proportions close to Formula IV.
  • a peak for the valacyclovir hydrochloride is readily evident in the upper curve at 195°C and a peak for gliceril benehate is evident at at 7O 0 C.
  • the lower DSC curve in figure 5 was generated after granulated this mixture with water.
  • the valacyclovir hydrochloride peak is visible, and there is a broad endothermic effect in the temperature range of 100-120 0 C probably due to the aggregation of the celluloses.
  • Figure 6 depicts the DSC curve of a mechanical mixture of all the components present in the dosage form.
  • a mixture was made of valacyclovir hydrochloride and Magnolia starch; then the solid mixture was wetted with a hydro-alcoholic solution 1 :9 in methocel.. All the components were kneaded and left in ambient conditions to be dried.
  • valacyclovir hydrochloride shows a peak at 195°C with low intensity probably due to partial decreasing of crystallinity. There is a broad endothermic effect in the temperature range of 100- 120°C probably due to the interaction of celluloses with water (inclusion water).
  • Figure 7 depicts the DSC curve for a mechanical mixture with all the components present in the dosage form.
  • a valacyclovir hydrochloride peak is evident at 195°C and a gliceril benehate peak is evident at 70°C. No interaction peaks are evident.
  • the lower curve in figure 7 is generated.
  • the valacyclovir hydrochloride peak is visible, but with lower intensity, and there is a broad endothermic effect in the temperature range of 100-120°C probably due to the aggregation of the celluloses.
  • no interactions among valacyclovir hydrochloride and excipients are detected.
  • Figure 8 depicts the DSC curve for a VALA III /44 tablet (final formulation before film coating).
  • a peak for valacyclovir hydrochloride is evident at 195°C and one for gliceril benehate is evident at 70°C. No interaction peaks are observed.
  • the mixture was then granulated with water and analysed by DSC to produce the lower curve in figure 8.
  • the valacyclovir hydrochloride peak is very visible, but with lower intensity, and there is a broad endothermic effect in the temperature range of 100-120°C probably due to the aggregation of the celluloses, or due to the Opadry effect.
  • the study here was a pilot, four periods, four sequences, cross-over, controlled, block randomized, single dose bioequivalence study, and employed 77 healthy fasting volunteer patients.
  • the two test formulations were Valacyclovir 1000 mg coated tablets and 2x500 mg coated tablets, and were compared to Zelitrex ® (U.S. product) and Valtrex ® (European product) tablets as reference 1000 mg formulations.
  • 5 ml blood samples were drawn before valacyclovir administration (time 0.0), and at 0.5; 0.75; 1.0; 1.33; 1.67; 2.0; 2.5; 3.0; 4.0; 6.0; 8.0; 10.0; 12.0; 16.0; and 24 hours past dose.
  • AUCo- m f (from time 0 to infinite) area under the concentration-time curve integrated from the plasma concentrations extrapolating the terminal elimination phase;
  • AUC 0-t area under the concentration-time curve integrated, by the trapezoidal rule, from plasma concentrations between time 0 to the last quantifiable sample;
  • C ma ⁇ peak plasma drug concentration, obtained directly from the data, without interpolation;
  • T max time of peak drug concentration, obtained directly from the data, without interpolation;
  • MRT mean residence time, calculated as AUMCinf/AUCinf, where AUMCin

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Abstract

La présente invention concerne des formes galéniques solides pour administration par voie orale de chlorhydrate de valacyclovir, en particulier des comprimés, qui ont été mises au point en utilisant des techniques de granulation par voie humide qui (i) sont stables dans le temps, (ii) satisfont aux exigences élevées de manipulation physique, (iii) possèdent une biodisponibilité optimale et (iv) permettent l'intégration de grandes proportions de chlorhydrate de valacyclovir dans la formulation totale.
PCT/EP2007/000966 2006-02-06 2007-02-05 Formulations solides de chlorhydrate de valacyclovir Ceased WO2007090595A1 (fr)

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US60/765,789 2006-02-06

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PCT/EP2007/000966 Ceased WO2007090595A1 (fr) 2006-02-06 2007-02-05 Formulations solides de chlorhydrate de valacyclovir

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009037449A1 (fr) * 2007-09-18 2009-03-26 Cipla Limited Compositions pharmaceutiques solides comprenant un ou plusieurs inhibiteurs du virus de l'herpès et un ou plusieurs inhibiteurs de la transcriptase inverse
WO2009049648A3 (fr) * 2007-10-17 2009-10-01 Pharmathen S.A. Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci
WO2016015799A1 (fr) * 2014-07-31 2016-02-04 Pharmathen S.A. Comprimé à mâcher pédiatrique contenant un agent antiviral et son procédé de préparation
WO2020049536A1 (fr) * 2018-09-07 2020-03-12 Jubilant Generics Limited Compositions pharmaceutiques de valacyclovir ou de ses sels pharmaceutiquement acceptables

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022082A1 (fr) * 1995-01-20 1996-07-25 The Wellcome Foundation Limited Comprimes de valaciclovir contenant du dioxyde de silicium colloidal
WO1997025989A1 (fr) * 1996-01-19 1997-07-24 Glaxo Group Limited Utilisation de valaciclovir dans la fabrication d'un medicament destine au traitement de l'herpes genital
WO2003017981A1 (fr) * 2001-08-29 2003-03-06 Ranbaxy Laboratories Limited Formulation a liberation controlee de clarithromycine ou de tinidazol
WO2004000265A2 (fr) * 2002-06-24 2003-12-31 Ranbaxy Laboratories Limited Procede de preparation de formulations solides de comprimes de chlorhydrate de valacyclovir
WO2004037263A1 (fr) * 2002-10-22 2004-05-06 Ranbaxy Laboratories Limited Compositions pharmaceutiques de ganciclovir
EP1541133A1 (fr) * 2003-12-09 2005-06-15 Helm AG Formulation pharmaceutique de valaciclovir

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022082A1 (fr) * 1995-01-20 1996-07-25 The Wellcome Foundation Limited Comprimes de valaciclovir contenant du dioxyde de silicium colloidal
WO1997025989A1 (fr) * 1996-01-19 1997-07-24 Glaxo Group Limited Utilisation de valaciclovir dans la fabrication d'un medicament destine au traitement de l'herpes genital
WO2003017981A1 (fr) * 2001-08-29 2003-03-06 Ranbaxy Laboratories Limited Formulation a liberation controlee de clarithromycine ou de tinidazol
WO2004000265A2 (fr) * 2002-06-24 2003-12-31 Ranbaxy Laboratories Limited Procede de preparation de formulations solides de comprimes de chlorhydrate de valacyclovir
WO2004037263A1 (fr) * 2002-10-22 2004-05-06 Ranbaxy Laboratories Limited Compositions pharmaceutiques de ganciclovir
EP1541133A1 (fr) * 2003-12-09 2005-06-15 Helm AG Formulation pharmaceutique de valaciclovir

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009037449A1 (fr) * 2007-09-18 2009-03-26 Cipla Limited Compositions pharmaceutiques solides comprenant un ou plusieurs inhibiteurs du virus de l'herpès et un ou plusieurs inhibiteurs de la transcriptase inverse
WO2009049648A3 (fr) * 2007-10-17 2009-10-01 Pharmathen S.A. Composition pharmaceutique améliorée contenant un agent antiviral et procédé de préparation de celle-ci
WO2016015799A1 (fr) * 2014-07-31 2016-02-04 Pharmathen S.A. Comprimé à mâcher pédiatrique contenant un agent antiviral et son procédé de préparation
WO2020049536A1 (fr) * 2018-09-07 2020-03-12 Jubilant Generics Limited Compositions pharmaceutiques de valacyclovir ou de ses sels pharmaceutiquement acceptables

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