Valacyclovir oral suspensions, their preparation, storage and use

Abstract

The present invention provides an orally administrable, aqueous, valacyclovir suspension having immediate release characteristics in acidic environment below pH 2; comprising crystalline valacyclovir hydrochloride hydrate loaded onto a cationic ion exchange resin particle (preferably of methacrylic acid copolymer with divinyl benzene), having carboxylic acid functional groups in a valacyclovir hydrochloride to IER weight / weight ratio of 1:0.4-1:0.6. The present invention also provides a powder for the preparation of the valacyclovir oral suspension, together with methods for the preparation of the powder, the suspension, their storage and use.

Description

[0001] VALACYCLOVIR ORAL SUSPENSIONS,

[0002] THEIR PREPARATION, STORAGE AND USE

[0003] TECHNICAL FIELD

[0004] The present invention relates an orally administrable, aqueous, valacyclovir suspension comprising a valacyclovir resinate. Release of the valacyclovir from the resinate is triggerable by an acidic pH, as encountered in the stomach.

[0005] The orally administrable, aqueous valacyclovir resinate suspension according to an embodiment of the invention is advantageous for use in paediatric or geriatric patients as it overcomes difficulties with swallowing tablets. The liquid form also provides a form that is dose titratable according to body weight. Furthermore, the valacyclovir resinate suspension according to an embodiment of the invention has a behaviour similar to Valtrex® tablets.

[0006] The invention further relates to the preparation, storage and use of the valacyclovir resinate suspension; as well as to the valacyclovir resinate involved.

[0007] The invention provides an easy-to-use method for the preparation of the valacyclovir resinate suspension, as well as the related powder for oral suspension and valacyclovir resinate.

[0008] BACKGROUND

[0009] Valacyclovir is a well-known prodrug of acyclovir. It is known for use in the treatment of herpes virus infections. Valacyclovir is often used as hydrochloride salt. US5879706 and US6849736 disclose that valacyclovir hydrochloride is available in several crystalline forms, in addition to an amorphous form. Crystalline forms include an anhydrous and hydrate forms.

[0010] The commercially available dosage form of valacyclovir are blue film-coated tablets comprising valacyclovir hydrochloride as active pharmaceutical ingredient. To our understanding, the valacyclovir hydrochloride used is preferably the anhydrous crystalline form, meaning less than 3 % w / w water, as described in US5879706. Valacyclovir tablets are sold under the tradename Valtrex®. Each tablet contains 500 mg or 1000 mg valacyclovir (expressed as valacyclovir base equivalents). While the Valtrex® oral tablets can be administered as an extemporaneously prepared suspension, the suspension istedious to prepare, requires a special suspension base liquid, contains a colorant, and inuse stability is limited.

[0011] When in need of a liquid formulation for oral dosing, the approved Valtrex® product label advises on an extemporaneous preparation of 25 or 50 mg / ml oral suspensions in lots of 100 ml. Hereto Valtrex® 500 mg tablets are ground into a fine powder which is to be combined with a cherry flavour and a Suspension Structured Vehicle. These ingredients may not be readily available. Following the preparation in a mortar, the compounded suspension is transferred to a container for storage. The compounded valacyclovir oral suspension is to be stored between 2-8 °C (cold storage) for at most 28 days. There is a need for a more convenient method of preparation and storage. In addition, there could be further improvement of palatability.

[0012] Fish et al. (1999) disclosed stability studies of valacyclovir hydrochloride in three commonly used syrups. Valacyclovir (from caplets) was suspended in Ora-Sweet, Ora-Sweet SF, and Syrpalta Humco Laboratory syrup. The syrups were extemporaneously compounded to yield a final concentration of valacyclovir 50 mg / ml as the hydrochloride salt. The suspensions were stored at 4 °C in amber glass bottles. Valacyclovir concentrations were below 90% by day 21 in some individual samples of suspensions prepared with Ora-Sweet (SF). The Syrpalta-based suspensions were reported to be stable for at least 35 days.

[0013] Bastiaans et al. (2016) reported on the preparation of 20 mg / ml valacyclovir solutions based on valacyclovir HCI.1H2O, glycerol (42.5%, citric acid, disodium hydrogen phosphate and water with pH 3.5 as target. These formulations were reported to have a shelf life of at least 6 months. The formulation however failed to meet the criteria for bioequivalence to the approved Valtrex® tablet reference product.

[0014] In 2017 Bastiaans et al. reported results of follow-on research on palatability of extemporaneously prepared solutions. They were found non-inferior to suspensions prepared from crushed tablets.

[0015] As taste may influence acceptability and patient compliance substantially, especially in children, there remains a need for a liquid formulation that is bioequivalent and palatable. For pediatric use it is also of interest to have a more concentrated product so volumes to be administered can be kept limited. It may also be useful to have a formulation without colorant.In W02016 / 008560 powders for oral suspension are disclosed based on hydrated valacyclovir hydrochloride and an ion exchange resin. Indion 204 was identified as the preferred candidate resin in combination with a 1:0.8 and 1:1 drug to resin ratio due to their lower drug degradation effect. 50 and 100 mg / ml formulations were prepared. A non-acidic pH and taste were targeted. For this purpose, the pH adjusting agents NaOH or trisodium citrate dihydrate were used. It is desirable to have further improvements as NaOH is difficult to handle (exothermic reactions) and tri-sodium citrate dihydrate amounts were high. In addition, palatability may require more work.

[0016] The objective of the present invention is to find a solution to at least one of the problems described above. Particularly, the objective of the present invention is to provide a convenient, flexible, stable dosage form for patients who have difficulty swallowing tablets or / and need dose titration. Ideally, the invention provides a product with similar exposure to acyclovir as the reference listed drug Valtrex® (bioequivalent). It is also an objective to provide a palatable formulation, especially for paediatric patients. A product according to the invention needs to have a commercially viable or long shelf life in the dry state so that product can be dispensed off the shelf. Also, a relevant in-use stability is of importance.

[0017] SUMMARY OF THE INVENTION

[0018] In a first aspect, the invention provides a valacyclovir resinate comprising crystalline valacyclovir hydrochloride hydrate (API) loaded onto a cationic ion exchange resin particle (of a methacrylic acid copolymer with divinyl benzene), having carboxylic acid functional groups (IER), in a valacyclovir hydrochloride to IER weight-to-weight ratio of 1:0.4 to 1:0.6, preferably 1:0.5, wherein the chloride content is 9.0-11.0 % w / w on anhydrous and solvent-free basis with respect to API as determined by potentiometric titration.

[0019] The inventors have surprisingly found that the crystalline form of valacyclovir hydrochloride hydrate (API) used in the preparation of the resinate, maintains crystallinity in the resinate. The structure also still holds chloride and water. This may be advantageous for stability and homogeneity when the resinate is used in powders and liquid preparations.

[0020] Preferably the water content of the valacyclovir resinate according to an embodiment of the invention, is between 5 and 12% w / w, as determined by Karl Fisher water titration. Preferably the water content is determined on a 0.250 g sample.Preferably the hydrate is selected from a valacyclovir hydrochloride monohydrate, dihydrate or sesqui hydrate. Most preferably the valacyclovir hydrochloride hydrate is the valacyclovir hydrochloride sesquihydrate (form I).

[0021] Preferably, the valacyclovir resinate according to an embodiment of the invention comprises 2 theta characteristic peaks, measured by X-Ray Diffraction, as follows: 3.8°+ / -0.1, 8.7°+ / -0.1, 9.6°+ / -0.1, 10.7°+ / -0.1, 11.0°+ / -0.1, 13.5°+ / -0.2, 16.6°+ / -0.1, 20.3°+ / -0.2, 21.6°+ / -0.2, 24.1°+ / -0.1.

[0022] In a preferred embodiment the valacyclovir resinate according to an embodiment of the invention, was obtained from a process comprising the steps of:

[0023] - dry blending of crystalline valacyclovir hydrochloride hydrate and cationic ion exchange resin particles, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups,

[0024] - adding 10-30%, preferably 20%, water on solids content to the dry blend to obtain a premix,

[0025] - wet granulating the premix to obtain crystalline valacyclovir hydrochloride hydrate loaded on the cationic ion exchange resin particles,

[0026] - drying the granules obtained to a water content below 12% w / w as determined by Karl Fisher water titration; preferably the granules are dried for at least 20 min at a temperature of 40 to 50°C, preferably at 45°C.

[0027] Preferably the crystalline valacyclovir hydrochloride hydrate used in the dry blend has a water content of at least 4 % w / w.

[0028] In a further aspect, the invention provides a valacyclovir powder for the preparation of an orally administrable aqueous valacyclovir suspension, comprising: a valacyclovir resinate according to an embodiment of the invention.

[0029] More preferably the loaded porous ion exchange resin particle has a chloride ion content of 9.2-10.2 % w / w, as measured by potentiometric titration, and the water content of the powder is 5-12% w / w as measured by Karl Fisher water titration.

[0030] Most preferably the valacyclovir powder according to an embodiment of the invention, comprises valacyclovir hydrochloride in sesquihydrate form (form I) loaded on ion exchange resin particles of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups, and the powder is characterized by an XRD spectrumwith 2 theta characteristic peaks as follows: 3.6 + / -0.1, 8.6 + / - 0.2, 10.5 + / - 0.2, 10.9 + / -0.2, 21.4 + / - 0.2, 24.0 + / - 0.2, 26.7 + / -0.2 and resin peak 14.0-15.1 (halo) + / -0.2.

[0031] The powder according to an embodiment of the invention, is advantageous as it provides a formulation with long term stability which enables shipping and storage before dispensing.

[0032] In a further aspect the invention provides a method of manufacturing a valacyclovir powder according to an embodiment of the invention, comprising the steps of:

[0033] - dry blending of crystalline valacyclovir hydrochloride hydrate (API) and a cationic ion exchange resin particle (of methacrylic acid copolymer with divinyl benzene), having carboxylic acid functional groups (IER) in a weight-to-weight valacyclovir hydrochloride to IER ratio of 1:0.4 to 1:0.6; preferably of 1:0.5, - adding 10 to 30%, preferably 20%, water on solids content to the dry blend to obtain a premix,

[0034] - wet granulating the premix to obtain crystalline valacyclovir hydrochloride hydrate loaded on the ion exchange resin particle (of methacrylic acid copolymer with divinyl benzene,) having carboxylic acid functional groups, - drying the granules to a water content of at most 12% w / w as determined by Karl Fisher water titration, preferably the granules are dried for at least 20 min at a temperature of 40 to 50°C, preferably at 45°C,

[0035] - optionally milling the dried granules to a desired size,

[0036] - adding (dry) pharmaceutically acceptable auxiliary ingredients, such as a suspending agent, to the (milled) granules thereby obtaining a powdered blend with a water content of at most 12% w / w, as determined by Karl Fisher water titration.

[0037] Preferably the method of manufacturing a valacyclovir powder according to an embodiment of the invention, uses crystalline valacyclovir hydrochloride hydrate, form I, with a water content of 5 -11% w / w.

[0038] Preferably, the addition of pharmaceutically acceptable auxiliary ingredients includes the addition of a glidant and a lubricant.

[0039] More preferably the method of manufacturing a valacyclovir powder according to an embodiment of the invention, includes a step wherein multiple unit doses of the powdered blend are filled into a storage container, thereby occupying less than Vi of the fill volume of the storage container.In a preferred embodiment the storage container is of plastic and after filling the plastic storage container with the powdered blend, the plastic storage container is sealed with a heat-sealable lid.

[0040] In a further aspect, the invention provides an orally administrable, aqueous, valacyclovir suspension, comprising:

[0041] a pharmaceutically acceptable aqueous suspension base, and

[0042] a valacyclovir resinate according to an embodiment of the invention.

[0043] The availability of a liquid dosing form is advantageous for patients having problems swallowing. It is also advantageous where dose titration is required as a liquid dose can be easier adjusted than a tablet.

[0044] In a preferred embodiment of an orally administrable, aqueous valacyclovir suspension according to an embodiment of the invention, the chloride ion content of the suspension is 9.2-10.2% w / w on anhydrous and solvent-free basis with respect to API, as measured by potentiometric titration.

[0045] Preferably the pH of the aqueous valacyclovir suspension is 2.5-3.5; more preferably 2.6-3.4; even more preferably 2.7-3.3; most preferably 2.9-3.1.

[0046] Preferably a minimum of 90 % of valacyclovir present in the suspension is loaded onto the ion exchange resin particles. The absence of high amounts of unbound valacyclovir, which is a bitter active ingredient, is advantageous for the taste of the suspension.

[0047] In a preferred embodiment, the suspension has an in-use storage stability of 45 days at room temperature (20 to 25°C) and refrigerated conditions (0°C-8°C).

[0048] In a preferred embodiment, the valacyclovir suspension comprises 50 to 200 mg / ml valacyclovir (expressed in valacyclovir base equivalent).

[0049] In a preferred embodiment, the aqueous valacyclovir suspension comprises 0.5 to 10 mg / ml suspending agent; preferably xanthan gum.

[0050] In a preferred embodiment, the aqueous suspension comprises 0.1 to 10 mg / ml lubricant; preferably magnesium stearate.In a preferred embodiment, the orally administrable aqueous valacyclovir suspension comprises 1 to 10 mg / ml of one or more flavouring agents; preferably said one or more flavouring agents is banana flavour.

[0051] In a preferred embodiment, the orally administrable aqueous valacyclovir suspension has a white or off-white appearance.

[0052] In a preferred embodiment the orally administrable aqueous valacyclovir suspension, in a single unit dose administration of 1000 mg valacyclovir (expressed as valacyclovir base equivalent) in the form of the valacyclovir suspension, provides in a patient a bioequivalent pharmacokinetic profile for acyclovir by FDA requirements as compared to 1000 mg valacyclovir tablets (Reference Listed Drug).

[0053] In a more preferred embodiment the orally administrable aqueous valacyclovir suspension, in a single unit dose administration of 1000 mg valacyclovir (expressed as valacyclovir base equivalent) in the form of the valacyclovir suspension in a patient, provides a pharmacokinetic profile for acyclovir as measured in blood plasma of 3500 ng / ml to 5500 ng / ml Cmax and 14300 to 21505 ng.h / ml AUC(o-co), preferably 3900 ng / ml to 5050 ng / ml Cmax and 15850 to 19600 ng.h / ml AUC(o-co), even more preferably 3950 ng / ml to 5000 ng / ml Cmax and 15900 to 19550 ng.h / ml AUC(o-co).

[0054] In a preferred embodiment the orally administrable aqueous valacyclovir is for use in the treatment of a herpes virus infection in a patient in need thereof.

[0055] In a preferred embodiment the patient is administered 5 ml of the liquid suspension comprising 200 mg / ml valacyclovir (equivalents) or 20 ml of the liquid suspension comprising 50 mg / ml valacyclovir (equivalents).

[0056] In a preferred embodiment, the patient is a paediatric patient. In another preferred embodiment, the patient is a geriatric patient. In yet another preferred embodiment, the patient has difficulties swallowing.

[0057] In a preferred embodiment, the flavouring agent used for a paediatric patient, is banana flavour.

[0058] In a further aspect, the invention provides a storage container provided for holding multiple unit doses of a powder for oral suspension, the container comprising : a valacyclovir powder according to an embodiment of the invention in an amount for multiple unit dosing, wherein the amount for multiple unit dosing is 1 to 50 g, and the powder occupies at most 1 / 2 ofthe fill volume of the storage container, thereby providing for the addition of a pharmaceutically acceptable liquid suspension base for the preparation of the oral suspension in the storage container.

[0059] In a further aspect, the invention provides a kit of parts comprising the storage container according to an embodiment of the invention, an oral dosing syringe, a bottle adaptor for holding the container and the dosing syringe, and a leaflet with instructions for storage and use of the kit.

[0060] In a preferred embodiment, the kit is for use three times daily during a period of 5 days.

[0061] In a preferred embodiment, the instructions for storage include storage at room temperature (20°C to 25°C [68°F to 77°F]) for up to 45 days once the oral suspension is prepared.

[0062] In a further aspect, the invention provides a method of manufacturing an orally administrable liquid suspension according to any embodiment of the invention, comprising the steps of:

[0063] - providing a storage container holding a valacyclovir powder for the preparation of an oral suspension for multiple unit dosing according to an embodiment of the invention,

[0064] - adding a pre-determined volume of a pharmaceutically acceptable liquid suspension base, preferably water, to the storage container thereby obtaining the orally administrable liquid suspension.

[0065] Preferably, the valacyclovir suspension comprises 50 to 200 mg valacyclovir per ml suspension.

[0066] The liquid suspension prepared in the storage container of the powder, provides for multiple unit dosing and is ready-to-use. It is advantageous that the suspension can be prepared by simple addition of water, which is readily available. The storage container is turned into a multidose container of valacyclovir suspension.

[0067] BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 is a graphic representation of the XRD pattern of a valacyclovir resinate according to an embodiment of the invention (valacyclovir hydrochloride:IER ratio is 1:0.5).Figure 2 is a graphic representation of the FTIR pattern of a valacyclovir resinate according to an embodiment of the invention (valacyclovir hydrochloride:IER ratio is 1:0.5).

[0069] Figure 3 is a graphic representation of the pharmacokinetic profile of means for acyclovir, as measured in plasma samples of 30 subjects over a period of 24 hours. Squares = R fast, triangles = T fast, circles = Tfed.

[0070] Figure 4 is a graphic representation of the pharmacokinetic profile of means for valacyclovir, as measured in plasma samples of 30 subjects over a period of 24 hours. Squares = R fast, triangles = T fast, circles = Tfed.

[0071] DETAILED DESCRIPTION OF THE INVENTION

[0072] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

[0073] The examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.

[0074] When introducing elements of the present disclosure or an aspect thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0075] The term "and / or" when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items. For example, the expression "A and / or B" is intended to mean either or both of A and B, i.e. A alone, B alone or A and B in combination. The expression "A, B and / or C" is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination.

[0076] About includes + / - 10% of the numerical value.

[0077] Ratios and percentages are generally expressed by weight (weight / weight) unless otherwise indicated.By the term "ready-to-use" as used herein is meant a liquid valacyclovir composition that does not need further preparation and can be directly administered orally to a patient.

[0078] By the term "multidose" as used herein, is meant more than one dose, meaning that multiple doses are contained.

[0079] The inventive formulations of the present invention are based on the development of a valacyclovir resinate, comprising an ion exchange resin of a specified type loaded with valacyclovir hydrochloride hydrate. The valacyclovir structure selected for loading is a valacyclovir hydrochloride hydrate. It is crystalline, with a rod-like structure, and water of crystallization. The ion exchange resin used is a porous structure of a crosslinked acrylic acid co-polymer or methacrylic acid copolymer with divinyl benzene. For interaction with the valacyclovir the ion exchange resin has carboxylic acid functional groups. Preferably the carboxylic acid functional groups are in H-form.

[0080]

[0081] The most preferred ion exchange resin used is a porous structure of a methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups. The unloaded resinate has an amorphous structure.

[0082] An ion exchange resin suitable for use in the present invention is AmberLite IRP64, commercially available from DuPont. It is a pharmaceutical grade cation exchange resin (polacrilex resin). It is insoluble, weakly acidic, hydrogen form, cation exchange resin supplied as a fine powder. The loss on drying is at most 5.0%. Extractable water is at most 2.0%. It is derived from a porous copolymer of methacrylic acid and divinylbenzene, and has carboxylic acid functional groups.

[0083] It was surprisingly found that the conditions described herein, resulted in valacyclovir resinate particles wherein the ion exchange resin is loaded with the crystalline valacyclovir structure with HCI and moisture being preserved. Chlorine groups or water molecules were not lost in the loading of the ion exchange resin. It was also surprising that the crystallinity of valacyclovir was maintained. Their presence was demonstrated using several analytical techniques, such XRD.Water of hydration content can be measured using Karl Fisher water titration as known by a person skilled in the art. The method is described in the U.S. and European Pharmacopoeia.

[0084] Chloride content can be measured using potentiometric titration as known by a person skilled in the art.

[0085] Hence, the valacyclovir loaded resinate does not correspond to a mere physical blend of resin particles and valacyclovir particles. The manufacturing process provided a different physical appearance. Hence, the resinate can be distinguished from a physical blend of resin particles and valacyclovir particles by microscopy. It was also established that hydrochloric acid and crystal lattice water could be preserved under selected manufacturing conditions described herein.

[0086] In a preferred embodiment, valacyclovir hydrochloride hydrate is the only active ingredient present in the resinate.

[0087] The process for the manufacturing of the valacyclovir loaded resinate particles is as follows:

[0088] select an amount of valacyclovir hydrochloric acid hydrate and a cationic resinate, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups, and make a dry blend;

[0089] - adding 10 to 30%, preferably 20%, water on solids content to the dry blend to obtain a premix,

[0090] wet granulating the premix to obtain crystalline valacyclovir hydrochloride dihydrate loaded on the ion exchange resin particles, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups,

[0091] drying the granules obtained to a water content below 12% w / w as determined by Karl Fisher water titration, preferably the granules are dried for at least 20 min at a temperature of 40 to 50 °C, preferably 45°C.

[0092] Addition of a lower amount of water, could lead to a less efficient loading of the resin particles. Addition of a much higher amount of water, requires more energy after the loading to remove excess water.

[0093] The process according to an embodiment of the invention is devoid of a washing step.Preferably the crystalline valacyclovir hydrochloride hydrate used in the dry blend has a water content of at least 5 % w / w and at most 11.0% w / w.

[0094] The invention, in a first aspect, provides an ion exchange resin particle comprising valacyclovir hydrochloride hydrate loaded onto a porous resinate, having carboxylic acid functional groups. Preferably the resinate has a backbone of methacrylic acid copolymer with divinyl benzene. This resinate is also known as a cationic ion exchange resin. Preferably the ion exchange resin is a weak cationic ion exchange resin. Most preferably the ion exchange resin is a weak cationic ion exchange resin in hydrogen form.

[0095] The structure of valacyclovir hydrochloride hydrate, is provided by Formula I.

[0096] O

[0097]

[0098] Formula I

[0099] The structure of the preferred resinate of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups, is provided by Formula II.

[0100]

[0101] Formula II

[0102] The proposed structure of valacyclovir hydrochloride hydrate loaded on the preferred resinate in a ratio of API to IER of 0.5, is shown in Formula III.

[0103]

[0104] . 2 HCI . x H2O

[0105] Formula III

[0106] An XRD spectrum of the active ingredient, the ion exchange resin and of the resinate, are provided in Figure 1. As active ingredient valacyclovir hydrochloride, form I, was preferably used.

[0107] Preferably, the valacyclovir resinate according to an embodiment of the invention comprises 2 theta characteristic peaks, measured by X-Ray Diffraction, as follows: 3.8°+ / -0.1, 8.7°+ / -0.1, 9.6°+ / -0.1, 10.7°+ / -0.1, 11.0°+ / -0.1, 13.5°+ / -0.2, 16.6°+ / -0.1, 20.3°+ / -0.2, 21.6°+ / -0.2, 24.1°+ / -0.1.

[0108] In a further aspect, the invention provides an orally administrable, aqueous, valacyclovir suspension, comprising:

[0109] a pharmaceutically acceptable aqueous suspension base, and

[0110] a valacyclovir resinate according to an embodiment of the invention.

[0111] In particular, the valacyclovir suspension comprises crystalline valacyclovir hydrochloride dihydrate (API) loaded onto a weak cationic ion exchange resin particle having carboxylic acid functional groups (IER) and the valacyclovir hydrochloride to IER w / w ratio in the complex is 1:0.5 (valacyclovir resinate).

[0112] Preferably the valacyclovir suspension comprises crystalline valacyclovir hydrochloride dihydrate (API) loaded onto a porous ion exchange resin particle of methacrylic acidcopolymer with divinyl benzene, having carboxylic acid functional groups (IER) and the valacyclovir hydrochloride to IER w / w ratio in the complex is 1:0.5 (valacyclovir resinate).

[0113] In a preferred embodiment the chloride ion content of the suspension is 9.2-10.2% w / w, on anhydrous and solvent-free basis with respect to API, as measured by potentiometric titration.

[0114] In a preferred embodiment the pH of the aqueous valacyclovir suspension is 2.5-3.5.

[0115] Preferably the aqueous valacyclovir according to an embodiment of the invention is free of pH adjusting agent.

[0116] In a preferred embodiment a minimum of 90 % of valacyclovir present in the suspension is loaded onto the ion exchange resin particles.

[0117] The orally administrable, aqueous valacyclovir suspension according to an embodiment of the invention, preferably has a storage stability of 45 days at room temperature (20°C to 25°C) and at refrigerated conditions (0°C-8°C).

[0118] Preferably the valacyclovir suspension comprises 50 to 200 mg / ml valacyclovir (expressed in valacyclovir base equivalent).

[0119] In a preferred embodiment, the oral suspension has an in-use stability of at least 30 days, more preferably at least 45 days, as measured at room temperature of 25°C and 60% Relative Humidity.

[0120] Preferably the aqueous suspension comprises a suspending agent; preferably xanthan gum. Preferably the amount of suspending agent in the valacyclovir suspension according to an embodiment of the invention is 0.5 to 10 mg / ml, more preferably 1 to 4 mg / ml.

[0121] Preferably the aqueous suspension base comprises a lubricant; preferably magnesium stearate. Preferably the amount of lubricant in the valacyclovir suspension according to an embodiment of the invention is 0.1 to 10 mg / ml mg / ml, more preferably 0.2 to 5 mg / ml, most preferably 0.3 to 2 mg / ml.

[0122] Preferably the orally administrable aqueous valacyclovir suspension according to an embodiment of the invention, comprises 1 to 10 mg / ml of one or more flavouring agents. Preferably the one or more flavouring agents is banana flavour.The orally administrable aqueous valacyclovir suspension according to an embodiment of the invention preferably has a white or off-white appearance.

[0123] In a preferred embodiment valacyclovir is the only active ingredient present in the suspension.

[0124] Preferably the valacyclovir resinate in the suspension was formed by wet granulation of a mixture of valacyclovir hydrochloride in hydrated form, water and porous ion exchange resin particles, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups, followed by a drying step until a water content of at most 12% w / w is obtained as determined by Karl Fisher water titration.

[0125] In a preferred embodiment the orally administrable aqueous valacyclovir suspension, in a single unit dose administration of 1000 mg valacyclovir (expressed as valacyclovir base equivalent), in the form of the valacyclovir suspension, provides in a patient a bioequivalent pharmacokinetic profile for acyclovir by FDA requirements as compared to 1000 mg valacyclovir tablets (Reference Listed Drug).

[0126] In a more preferred embodiment, the orally administrable aqueous valacyclovir suspension according to an embodiment of the invention, per single unit dose of 1000 mg valacyclovir (expressed as valacyclovir base equivalent) in a patient, provides a pharmacokinetic profile for acyclovir as measured in blood plasma of: an average maximum acyclovir blood plasma concentration of 3500 ng / ml to 5500 ng / ml Cmax and 14300 to 21505 ng.h / ml AUC(o-co), preferably 3900 ng / ml to 5050 ng / ml Cmax and 15850 to 19600 ng.h / ml AU o-co), even more preferably 3950 ng / ml to 5000 ng / ml Cmax and 15900 to 19550 ng.h / ml AUC(o-oo).

[0127] Preferably the orally administrable aqueous valacyclovir suspension according to an embodiment of the invention is for use in the treatment of a herpes virus infection in a patient in need thereof. The herpes virus infection is preferably selected for a varicella zoster virus infection-herpes zoster, a herpes simplex virus infection or a cytomegalovirus infection.

[0128] Preferably the patient is administered 5 ml of the liquid suspension comprising 200 mg / ml valacyclovir (expressed in valacyclovir base equivalents). Alternatively, the patient is administered 20 ml of the liquid suspension comprising 50 mg / ml valacyclovir (expressed in valacyclovir base equivalents).Preferably the liquid suspension is orally administered at least three times a day for a period of 5 days.

[0129] In a preferred embodiment of the invention, the patient is a paediatric patient.

[0130] In a third aspect, the invention provides a valacyclovir powder for the preparation of an orally administrable aqueous valacyclovir suspension according to an embodiment of the invention, comprising:

[0131] at least one ion exchange resin particle,

[0132] and a valacyclovir hydrochloride hydrate,

[0133] characterized in that,

[0134] the valacyclovir powder comprises crystalline valacyclovir hydrochloride dihydrate loaded onto a cationic ion exchange resin particle, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups (valacyclovir resinate) and the valacyclovir hydrochloride weight to IER weight ratio in the complex is 1:0.4 to 1:0.6; preferably 1:0.5.

[0135] In a preferred embodiment the loaded porous ion exchange resin particle has a chloride ion content of 9.2-10.2% w / w, on anhydrous and solvent-free basis with respect to API as measured by potentiometric titration, and the water content of the powder is 5-12% w / w. Water content is determined by Karl Fisher water titration.

[0136] Most preferably the valacyclovir powder according to an embodiment of the invention, comprises valacyclovir hydrochloride in sesquihydrate form (form I) loaded onto a weak cationic ion exchange resin particle of methacrylic acid copolymer with divinyl benzene having carboxylic acid functional groups and is characterized by an XRD spectrum with 2 theta characteristic peaks as follows: 3.6 + / -0.1, 8.6 + / - 0.2, 10.5 + / - 0.2, 10.9 + / -0.2, 21.4 + / - 0.2; 24.0 + / - 0.2; 26.7 + / -0.2. and a resin peak of 14.0-15.1 (halo) + / -0.2.

[0137] In a preferred embodiment the valacyclovir resinate is present in the powder for at least 50 % w / w. In a preferred embodiment valacyclovir is the only active ingredient present in the powder.

[0138] In a further embodiment, the valacyclovir powder for oral suspension further comprises at least one additional pharmaceutical excipient selected from suspending agents, preservatives, sweeteners, glidants, flavoring agents, lubricants and mixtures thereof.In an embodiment, the solid composition comprises at least one suspending agent. Examples of suspending agents include, but are not limited to, gums such as xanthan gum, carrageenan gum, acacia, guar gum, locust bean gum, gum tragacanth; celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, mixture of microcrystalline cellulose and carboxymethylcellulose 25 (Avicel RC); polyvinylpyrrolidone; alginic acid; alginate; sodium alginate, bentonite; 30 carbomers (carboxyvinyl polymers) such as those available under the trade name Carbopol , cetostearyl alcohol; maltodextrin; polyvinyl alcohol; colloidal silicon dioxide, propylene glycol; sodium starch glycolate; starch; acrylic polymers and mixtures thereof.

[0139] In a preferred embodiment, the at least one suspending agent is xanthan gum.

[0140] In a further embodiment, the valacyclovir powder for oral suspension has a resuspend ability time of 5 to 20 seconds. The 50 mg / ml suspension typically had a resuspend ability time of 6-9 seconds, whereas the 200 mg / ml valacyclovir powder for oral suspension typically had a resuspend ability time of 13-15 seconds.

[0141] In a more preferred embodiment, the xanthan gum is present in an amount of 1 to 100 mg per gram powder, even more preferably 5 to 50 mg per gram powder, most preferably 7 to 25 mg per gram powder, typically around 10 mg per gram powder.

[0142] Preferably the powder for oral suspension comprises at least one sweetener. Preferably the at least one sweetener is selected from sucrose, dextrose, sucralose, sorbitol, neotame, aspartame, Acesulfame K, fructose, mannitol, invert sugar, saccharin sodium, aspartame and mixtures thereof.

[0143] In a preferred embodiment, the at least one sweetener is sucralose.

[0144] In a more preferred embodiment, the amount of sweetener comprised in the powder for oral solution is 0.1 to 50 mg per g powder. Even more preferably the amount of sweetener is 1 to 40 mg per g powder, most preferably the amount of sweetener is 25 to 30 mg per g powder.

[0145] More preferably the sweetener is sucralose. In a most preferred embodiment, the powder for oral solution comprises 25 to 30 mg sucralose per g powder; most preferably 28 mg sucralose per gram powder.In a preferred embodiment, the powder for oral solution comprises at least one preservative. Examples of preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and mixtures thereof.

[0146] In a more preferred embodiment, the powder for oral suspension comprises methylparaben and propylparaben.

[0147] In a most preferred embodiment, the powder for oral suspension comprises 50-75 mg methylparaben and 40-60 mg propylparaben per gram powder.

[0148] More preferably the powder for oral suspension comprises 55-70 mg methylparaben per gram powder, even more preferably 58-65 mg methylparaben per gram powder, most preferably around 59-61 mg methylparaben per gram powder.

[0149] More preferably the powder for oral suspension comprises 45-55 mg propylparaben per gram powder, even more preferably 48-54 mg propylparaben per gram powder, most preferably around 49-51 mg propylparaben per gram powder.

[0150] In a preferred embodiment, the powder for oral suspension comprises a glidant. Examples of glidants include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof.

[0151] In a more preferred embodiment, the powder for oral suspension comprises talc.

[0152] In an even more preferred embodiment, the powder comprises 20 - 30 mg talc per gram of powder. Most preferably the powder comprises 22-28 mg talc per gram powder. Typically, the powder according to an embodiment of the invention comprises around 25 mg talc per gram of powder.Talc can be added to improve the flow properties of the powder for oral suspension. It may improve the accuracy of dosing.

[0153] In a preferred embodiment, the powder for oral suspension comprises a flavoring agent.

[0154] Examples of flavoring agents include, but are not limited to, banana, lemon, orange, grape, lime, grapefruit, vanilla, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, wild cherry, walnut, chocolate, pineapple, apricot, synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of Wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter to almonds, mint and cassia oil, maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof. Preferably, the flavoring agent is selected from cherry, banana and orange. Even more preferably the flavoring agent is selected from cherry and banana.

[0155] Preferably the flavoring agent comprised in the powder for oral suspension, according to an embodiment of the invention, is banana.

[0156] More preferably the powder for oral suspension comprises 10-20 mg banana flavoring agent per gram of powder. Even more preferably the powder for oral suspension comprises 12-18 mg banana flavoring agent per gram of powder. Most preferably the powder for oral suspension comprises around 15 mg banana flavor per gram of powder.

[0157] In a preferred embodiment, the powder for oral suspension comprises a lubricant.

[0158] Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures of magnesium stearate with sodium lauryl sulfate, talc, stearic acid, waxes, glycerides, light mineral oil, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycols, alkyl sulfates, or sodium benzoate and mixtures thereof.

[0159] In a preferred embodiment the lubricant is magnesium stearate.

[0160] More preferably the powder for oral suspension comprises 1-10 mg lubricant, preferably magnesium stearate, per gram of powder. Even more preferably the powder for oral suspension comprises 2-8 mg lubricant per gram of powder. Most preferably the powder for oral suspension comprises 4-6 mg of lubricant per gram of powder.In a most preferred embodiment, the composition of the invention is free of pH adjusting agent.

[0161] In a preferred embodiment, the composition of the invention comprises a pH adjusting agent. Examples of pH adjusting agents include, but are not limited to buffers: citrate buffers, phosphate buffers, monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate; hydroxide: sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, or other agents suitable for raising the pH of aqueous solutions; acids; hydrochloric acid, sulfuric acid, acetic acid or other acid.

[0162] In a preferred embodiment, the composition of the invention is free of sodium hydroxide and citrate buffer such as tri-sodium citrate dihydrate.

[0163] In a more preferred embodiment, a powder for oral suspension comprises per gram powder:

[0164] 750-850 mg valacylovir resinate,

[0165] 20-30 mg suspending agent, preferably xanthan gum,

[0166] 10-20 mg flavouring agent, preferably banana,

[0167] 3-6 mg lubricant, preferably magnesium stearate.

[0168] More preferably the powder for oral suspension comprises per gram powder 800-840 mg valacyclovir resinate.

[0169] In a further aspect, the invention provides a method of manufacturing a valacyclovir powder according to an embodiment of the invention, comprising the steps of:

[0170] - dry blending of crystalline valacyclovir hydrochloride dihydrate (API) and the cationic ion exchange resin particle, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups (IER) in a weight / weight valacyclovir hydrochloride / IER ratio of 1:0.5,

[0171] - adding 20% water on solids content to the dry blend to obtain a premix,

[0172] - wet granulating the premix to obtain crystalline valacyclovir hydrochloride dihydrate loaded on the ion exchange resin particle, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups,- drying the granules to a water content of at most 12% w / w as determined by Karl Fisher water titration, preferably the granules are dried for at least 20 min at a temperature of 45°C,

[0173] - optionally milling the dried granules to a desired size,

[0174] - adding (dry) pharmaceutically acceptable auxiliary ingredients, such as a suspending agent, to the (milled) granules thereby obtaining a powdered blend with a water content of at most 12% w / w, as determined by Karl Fisher water titration.

[0175] Preferably the ion exchange resin is a weak cationic ion exchange resin. Preferably the valacyclovir used is crystalline valacyclovir hydrochloride dihydrate with a water content of 6 -11% w / w.

[0176] Preferably the pharmaceutically acceptable auxiliary ingredients added include a glidant and a lubricant.

[0177] In a preferred embodiment, multiple unit doses of the powdered blend are filled in a storage container, thereby occupying less than Vi of the fill volume of the storage container. More preferably less than 4 / 10 of the storage container's fill volume is occupied by the powdered blend; more preferably less than 1 / 3 of the storage container's fill volume is occupied by the powdered blend. The remainder of the fill volume can be used to house the water for reconstitution of the powdered blend to a suspension.

[0178] Preferably in a method of manufacturing a valacyclovir powder according to an embodiment of the invention, the storage container is a plastic container and after filing with the powdered blend, the plastic container is sealed with a heat-sealable lid. The plastic can be High Density PolyEthylene or Polyester. The polyester is preferably Polyethylene terephthalate (PET). More preferably the PET is transparent.

[0179] In a preferred embodiment the powder for oral suspension has a storage stability when stored in a glass or plastic bottle of at least 3 months, more preferably at least 6 months, most preferably of at least 12 months, measured at 40°C and 75% Relative Humidity.

[0180] In a further aspect the invention provides a valacyclovir resinate comprising crystalline valacyclovir hydrochloride dihydrate (API) loaded onto a porous ion exchange resin particle of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups (IER); in a valacyclovir hydrochloride to IER weight / weight ratio of 1:0.5.Preferably the chloride content is 9.0 to 11.0 % w / w on anhydrous and solvent-free basis with respect to API and the water content is at most 12% w / w, more preferably 8-9 % w / w, as determined by Karl Fisher water titration.

[0181] In a further aspect, the invention provides a storage container provided for holding multiple unit doses of a powder for oral suspension, the container comprising:

[0182] a valacyclovir powder according to an embodiment of the invention in an amount for multiple unit dosing,

[0183] wherein the amount for multiple unit dosing is 1 to 50 g, and

[0184] the powder occupies at most 1 / 2 of the fill volume of the storage container, thereby providing for the addition of a pharmaceutically acceptable liquid suspension base for the preparation of the oral suspension in the storage container.

[0185] The invention also provides a kit of parts comprising the storage container according to an embodiment of the invention, an oral dosing syringe, a bottle adaptor for holding the container and the dosing syringe, and a leaflet with instructions for storage and use of the kit.

[0186] In a preferred embodiment, the kit according to an embodiment of the invention, is for use three times daily during a period of 5 days.

[0187] The kit of parts preferably has a leaflet for storage and use of the kit, wherein instructions for storage include storage at room temperature (20°C to 25°C [68°F to 77°F]) for up to 45 days once the oral suspension is prepared.

[0188] In a further aspect, the invention provides a method of manufacturing an orally administrable liquid suspension according to an embodiment of the invention, comprising the steps of:

[0189] - providing a storage container holding a valacyclovir powder for the preparation of an oral suspension for multiple unit dosing according to an embodiment of the invention,

[0190] - adding a pre-determined volume of a pharmaceutically acceptable liquid suspension base, preferably water, to the storage container thereby obtaining the orally administrable liquid suspension.

[0191] Preferably the orally administrable liquid suspension obtained comprises 50 to 200 mg valacyclovir / ml.The liquid suspension prepared in the storage container of the powder, provides for multiple unit dosing and is ready-to-us. It is advantageous that the suspension can be prepared by simple addition of water, which is readily available. The storage container is turned into a multidose container of valacyclovir suspension.

[0192] EXAMPLES

[0193] Valacyclovir resinate

[0194] Example 1

[0195] Crystalline valacyclovir hydrochloride hydrate, form I, was purchased from different suppliers.

[0196] Porous ion exchange resins were purchased from different commercial suppliers. The resin selected was a weak acid cation type ion exchange resin. The specific weak acid cation type ion exchange resin selected were particles of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups. It is commercially available, for instance from DuPont under the tradename AmberLite IRP64. AmberLite IRP64 can be identified by Infrared Spectroscopy. Its IR spectrum is provided on the Datasheet of the product, which is incorporated herein by reference.

[0197] Crystalline valacyclovir hydrochloride hydrate was dry blended (i.e. without the use of liquid) with the AmberLite IRP64, in a ratio of valacyclovir hydrochloride to AmberLite IRP64 of 1:0.5. The water content of valacyclovir hydrochloride was not taken into account.

[0198] To the blend, water was added to obtain a premix. Water was added in a quantity of 20% on solids content.

[0199] The premix was wet granulated and valacyclovir resinate granules were obtained. The granules comprise valacyclovir hydrochloride loaded on ion exchange resin.

[0200] The granules were dried to remove excess water content. The target water content is below 12% w / w and above 5% w / w. For the determination of the water content Karl Fisher water titration was used. This also measures crystal water. A drying time of at least 20 min at a temperature of 45°C was used.

[0201] XRD analysis was conducted on API from different vendors, on different ion exchange resins and on the valacyclovir resinate, according to an embodiment of the invention. The results are summarized in Tables 1-3. XRD = X-Ray diffraction.Based on data from DSC and XRD studies, it was concluded that the valacyclovir resinate is loaded with the crystalline HCI salt of valacyclovir in hydrate form, particularly the sesquihydrate (form I). It was a surprise to find that the hydrochloride and crystal water were preserved after complexation.

[0202] Table 1: XRD analysis of crystalline valacyclovir hydrochloride hydrate

[0203]

[0204] Table 2: XRD analysis of ion exchange resins

[0205]

[0206] Amberlite IRP69 is a strongly acidic, sodium form cation ion exchange resin.

[0207] Table 3: XRD analysis of valacyclovir resinate according to embodiments of the invention - APLAmberlite IRP64 complexes

[0208]

[0209] Both materials prepared (Table 3) conformed with the XRD pattern of valacyclovir hydrochloride hydrate from the supplier and to that of the Form I polymorph as described in literature. No characteristic peaks of alternative polymorphs (i.e. Form II, IV, V) were identified. It was concluded that the API maintained crystallinity.

[0210] The typical X-ray diffraction (XRD) pattern for a valacyclovir resinate according to an embodiment of the invention, for an API: Amberlite IRP64 complex with API:IER ratio 1:0.5 is provided in Figure 1.

[0211] The typical FTIR pattern for a valacyclovir resinate according to an embodiment of the invention, for an API: Amberlite IRP64 complex with API:IER ratio 1:0.5 is provided in Figure 2.

[0212] Valacyclovir oral suspensions and powders for their preparation.

[0213] The most preferred list of ingredients and concrete examples are provided below.

[0214] Table 4 provides the qualitative composition of preferred embodiments according to the invention. The table also lists the function of the ingredients selected.

[0215] Table 4: Qualitative composition of valacyclovir powders for oral suspension, according to the invention

[0216]

[0217] Example 2: Powders for oral suspension and suspension prepared thereof

[0218] In a first example a preferred powder composition and related suspension prepared thereof, are provided. The composition of the powder for oral suspension and resulting suspension, are provided in Table 5.

[0219] The powder has a water content of not more than 12.0% w / w, as determined by Karl Fisher water titration. The powder was stored in a container. The total fill volume of the container was 240 ml.

[0220] The round bottle container was made of plastic, in particular High-Density PolyEthylene (HDPE). The plastic bottle had a screw thread for fitting of a closure. After containers were filled, they were fitted with a screw cap with child-resistant closure. The volume of the container is selected to house a multiple of unit doses, i.e. a multidose bottle.

[0221] The oral suspension is prepared by the addition of water to the powder. 150 ml of water was added to the container filled with powder occupying less than half of the fill volume.

[0222] The pH of the resulting suspension was 2.5 to 3.5.

[0223] Table 5: Quantitative composition of 50 mg / ml valacyclovir oral suspension and powder to prepare suspension

[0224]

[0225]

[0226] aThe valacyclovir HCI used is a crystalline, form I, with a 5-11% moisture content.

[0227] Weights of valacyclovir HCI and valacyclovir presented in the table above are based on the amount of valacyclovir HCI or valacyclovir (respectively) and do not account for weight due to water content.

[0228] bMethacrylic acid copolymer with divinyl benzene

[0229] Example 3 : 200 mg / ml powder for oral suspension and suspension prepared thereof

[0230] In a second example a valacyclovir powder for preparation of an oral suspension of increased strength is provided. The composition is provided in Table 5. The pH of the suspension was 2.5 to 3.5.

[0231] Table 6: Quantitative composition of 200 mg / ml valacyclovir oral suspension and powder to prepare suspension

[0232]

[0233]

[0234] cThe valacyclovir HCI used is a crystalline, form I, with a 5-11% moisture content.

[0235] Weights of valacyclovir HCI and valacyclovir presented in the table above are based on the amount of valacyclovir HCI or valacyclovir (respectively) and do not account for weight due to water content.

[0236] dMethacrylic acid copolymer with divinyl benzene

[0237] The XRD characteristic peaks for the valacyclovir powder compositions of Examples 2 and 3, are provided in Table 7.

[0238] Table 7 : XRD characteristic peaks of valacyclovir powder for oral suspension

[0239]

[0240]

[0241] Preparation of oral suspension

[0242] Example 4

[0243] The oral suspensions were prepared as follows:

[0244] 1. A prescribed amount of water was prepared. In particular, 140 ml of water for the 50 mg / ml suspension preparation or 100 ml of water for the 200 mg / ml suspension preparation were measured in a volumetric container.

[0245] 2. The bottle containing the powder was gently shaken to remove powder from the bottom of the bottle and the cap.3. The water was dispensed into the bottle. The bottle was closed with a child-resistant cap.

[0246] 4. The closed bottle was shaken for at least 20 seconds. The final volume was 150 ml for each strength (50 mg / ml and 200 mg / ml strength). The preparation provides a multidose amount of medicine.

[0247] 5. The suspension may be stored at room temperature (20°C to 25°C [68°F to 77°F]) for up to 45 days.

[0248] Dose homogeneity

[0249] To test suspension stability, a dose homogeneity study of reconstituted suspension was conducted. This study will evaluate both the intra- and inter-bottle homogeneity of the active ingredient after various storage conditions and durations. Specifically, the re-dispersibility at the top, middle, and bottom of each bottle is being assessed after storage under refrigerated (5°C ± 3°C) and room temperature conditions (20-25°C).

[0250] 10 bottles per strength per storage condition were used, as follows:

[0251] • 50 mg / mL : 0 days and 15 days (refrigerated and room temperature)

[0252] • 200 mg / mL : 0 days, 30 days (refrigerated and room temperature), 45 days (refrigerated and room temperature), and 60 days (refrigerated only)

[0253] The results of the test for the 200 mg / l strength, storage at room temp (20-25 0C) for 45 days, are presented in Table 8.

[0254] Table 8: Dose homogeneity of 200 mg / ml reconstituted valacyclovir powder for oral suspension according to an embodiment of the invention, after 45 days of suspension storage at room temperature (20 to 25°C)

[0255]

[0256]

[0257] RSD = relative standard deviation

[0258] Conclusion

[0259] Based on the interim analysis of 50 mg / ml after 15 days of storage at room temperature (Table 10) or refrigerated conditions (Table 11) and of analysis of 200 mg / ml at 30 and 45 days of storage, at room temperature (Table 10) or refrigerated conditions (Table 11), the mean % assay of valacyclovir across the top, middle, and bottom of the bottles was well within the acceptance criteria of 90.0-110.0% for both storage conditions.

[0260] In addition, the percent difference in the amount of valacyclovir between the top, middle, and bottom of each bottle is well below the acceptance criteria of 5.0% for both refrigerated and room temperature (Table 8) storage conditions.

[0261] Based on the current study, the homogeneity of the active ingredient within and between bottles is confirmed for all tested samples.

[0262] Storage stability - powder formulation

[0263] In order to evaluate the suitability of Amberlite IRP64 within finished product formula a stability study was performed for valacyclovir powder for oral suspension (API: Resin 1:0.5). Assay and Related substances were recorded at zero time and under 3 months and 6 months storage at long-term and accelerated conditions. The stability data are summarized in the following tables. Method I is based on USP monograph of Valacyclovir -Organic impurities procedure 2. Method II is based on DMF- RS method and the USP monograph -Assay / RS procedure. All critical quality attributes are well within acceptance criteria at 6 months storage under long term and accelerated storage conditions.Table 9: Result of storage stability study on powder

[0264]

[0265] In-use stability of suspensions

[0266] An in-use stability study helps determine the period during which a multiple-dose drug product remains acceptable in terms of quality specifications after the container is opened. This information is critical for patients who use the product over an extended period, ensuring that they receive consistent quality and efficacy throughout the designated usage period. In-use stability was carried out to evaluate microbiological contamination, physical instability, chemical degradation, and also for patient compliance, regulatory requirements. In-use stability carried out for both the strength (50 mg / ml and 200 mg / ml) of one registration batch and the results were summarized in Tables 10 and 11.Table 10: In-use stability results of oral suspensions in ambient condition

[0267]

[0268]

[0269] Oral suspension - palatabilitv

[0270] Threshold of bitterness concentration of Examples 2 and 3 were determined by a panel of at least four volunteers. The volunteers were asked to hold ~2ml of test solutions in their mouth for 10 seconds before spitting it out. The test solutions comprised the samples listed in Table 7 and a sample of a surrogate solution. The volunteers were then asked to rate the taste of the compositions based on a taste evaluation scale wherein 1 means super bad taste, 2 bad taste, 3 maybe good or maybe bad, 4 good and 5 super good. To avoid bias between samples, the volunteers were asked to rinse their oral cavity with water at least five times, and a minimum gap of 10 minutes was maintained between two successive taste evaluations.

[0271] Taste results are shown in the following Table 12.

[0272] Table 12: Palatability results

[0273]

[0274] Samples according to an embodiment of the invention (Composition Example 2 & 3) presented excellent palatability in comparison to an extemporaneously prepared suspension from crushed Valtrex tablets in combination with SSV and cherry flavour.

[0275] Chloride content determination in powder for Oral Suspension

[0276] The chloride content of powders for Oral Suspension, according to an embodiment of the invention, was tested using potentiometric titration. The results were compared to chloride content determination carried out on the active ingredient before wet granulation.

[0277] The study showed that the crystalline valacyclovir hydrochloride hydrate, form I, had a chloride content of 9.7 to 9.8 % w / w.

[0278] The chloride content of the powder comprising the valacyclovir resinate according to an embodiment of the invention, had a chloride content of 9.6 to 9.9 % w / w.The chloride content is expressed on anhydrous and solvent-free basis with respect to API.

[0279] It was concluded that there is no loss of chloride in the manufacturing process.

[0280] The results are summarized in Table 13.

[0281] Table 13: Chloride content determination in valacyclovir powders according to an embodiment of the invention

[0282]

[0283] Bioequivalence studies

[0284] Example 5

[0285] An open label, randomized, two-period, two-sequence, crossover bioavailability study was conducted to assess the pharmacokinetic and safety profile of Valacyclovir Oral Suspension compared to Valtrex® tablets, in normal healthy subjects under fasting conditions.

[0286] In the study a Test Product, Valacyclovir Oral Suspension according to an embodiment of the invention, was compared versus the reference product Valtrex® Tablets.

[0287] Plasma samples were collected. They were assayed for acyclovir (AIR) and valacyclovir (VIR) content. In total, 29 subjects were included into the study and dosed. Samples were statistically evaluated according to the Study Protocol.

[0288] To assess the relative bioavailability of the Test Product versus the Reference Product, pharmacokinetic parameters AUC(o-t), AUC(o-co), and Cmax for acyclovir were used. Acyclovir was the primary analyte due to the rapid conversion of valacyclovir toacyclovir, resulting in acyclovir being the major circulating analyte. Pharmacokinetic parameters for valacyclovir are presented as supportive data.

[0289] The results obtained are summarized in Table 14.

[0290] The results confirmed that the 90% confidence intervals for Test (T) to Reference (R) ratios of the geometric least squares means for AUC(o-t), AUC(o-co), and Cmax for the primary metabolite acyclovir is within acceptance range from 80% to 125% when administered under fasting conditions.

[0291] Table 14: Summary of the comparative relative bioavailability data

[0292]

[0293] Example 6

[0294] An open label, randomized, three-period, three-sequence, crossover bioavailability study was conducted. Aim of the study was the assessment of the pharmacokinetic and safety profile of Valacyclovir oral suspension, according to an embodiment of the invention, compared to an extemporaneous suspension prepared from Valtrex® tablet material (Ref 1). The study was conducted in normal, healthy subjects under fasting conditions. In addition, the effect of food on the bioavailability of Valacyclovir Oral Suspension (200 mg / ml Test Product, Example 3) was investigated.

[0295] The primary objectives were to assess the relative bioavailability of acyclovir after the administration of Valacyclovir Oral Suspension (200 mg / ml) compared to an extemporaneous suspension prepared from Valtrex(R) 500 mg tablets, under fasted conditions, and to assess the food effect on bioavailability of acyclovir.The secondary objective was to assess the PK profile of valacyclovir after the administration of Valacyclovir Oral Suspension (200 mg / ml) compared to administration of an extemporaneous suspension from Valtrex® 500 mg tablets, under fasted conditions, and to assess the food effect on the bioavailability of valacyclovir.

[0296] Safety Objective was to evaluate the safety and tolerability of Valacyclovir Oral Suspension (Example 3 composition) under fasted and fed conditions.

[0297] The reference oral suspension was prepared as follows at time of dispensing, from Valtrex® Tablets 500 mg, a flavouring agent, and Suspension Structured Vehicle USP-NF (SSV):

[0298] - Prepare SSV according to the USP-NF [Ref 2].

[0299] - Using a pestle and mortar, grind the required number of Valtrex 500 mg tablets until a fine powder is produced (5 Valtrex tablets for 25 mg / ml suspension; 10 Valtrex Tablets for 50 mg / ml suspension).

[0300] - Gradually add approximately 5 ml aliquots of SSV to the mortar and triturate the powder until a paste has been produced. Ensure that the powder has been adequately wetted.

[0301] - Continue to add approximately 5 ml aliquots of SSV to the mortar, mixing thoroughly between additions, until a concentrated suspension is produced, to a minimum total quantity of 20 ml SSV and a maximum total quantity of 40 ml SSV for both the 25 mg / ml and 50 mg / ml suspensions.

[0302] - Transfer the mixture to a suitable 100 ml measuring flask.

[0303] - Transfer the flavouring agent to the mortar and dissolve in approximately 5 ml of SSV. Once dissolved, add to the measuring flask.

[0304] - Rinse the mortar at least 3 times with approximately 5 ml aliquots of SSV, transferring the rinsing to the measuring flask between additions.

[0305] - Make the suspension to volume (100 ml) with SSV and shake thoroughly to mix.

[0306] - Transfer the suspension to an amber glass medicine bottle with a child-resistant closure.

[0307] - The prepared suspension should be labelled with the following information "Shake well before using. Store suspension between 2 °C to 8 °C in a refrigerator. Discard after 28 days."A single dose of Test product fasted or Test product fed or Reference product fasted was administered in each of three Study Periods, with a 7-day wash-out period between treatments.

[0308] As reference product, Valtrex® tablets were used. VALTREX tablets are for oral administration. Each tablet contains 556.2 mg or 1.112 gram of valacyclovir hydrochloride, equivalent to 500 mg or 1 gram (respectively) of 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.

[0309] For each formulation, 23 blood samples of 2 ml each, were collected from each subject during each period at pre-dose (within 1 hour before dosing) and at and at 0.083, 0.167, 0.25, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.50, 4.00, 6.00, 8.00, 12.00, 16.00, and 24.00 hours after dosing. Plasma concentrations were determined by validated HPLC / MS / MS method.

[0310] The results of the comparative bioavailability test, in 30 patients, are summarized in Tables 15 and 16.

[0311] Table 15: Summary of comparative bioavailability data (N=30)

[0312]

[0313] Tmax median (range) obtained for the Test Product was 1.50 hours (0.75 to 2.50 hours) for acyclovir; 0.75 hours (0.33 - 1.17 hours) for valacyclovir. For the Reference Product the Tmax median (range) was 1.38 hours (0.75 - 2.50 hours) for acyclovir and 0.50 hours (0.25 - 1.75 hours) for valacyclovir.Table 16: Summary of food -effect assessment data (N=30); 200 mg / ml valacyclovir oral suspension, fed and fasted, vs Valtrex® administered as extemporaneously prepared suspension.

[0314]

[0315] Tmax median (range) obtained for the Test Product was 2.25 hours (0.55 to 2.77 hours) for acyclovir; 1.50 hours (0.17 - 2.50 hours) for valacyclovir. For the Reference Product the Tmax median (range) was 1.50 hours (0.75 - 2.50 hours) for acyclovir and 0.75 hours (0.33 - 1.75 hours) for valacyclovir.

[0316] The results are summarized in Figures 3 and 4.

[0317] Figure 3 shows the pharmacokinetic profile of means for acyclovir, as measured in plasma samples of 30 subjects over a period of 24 hours.

[0318] Figure 4 shows graphic representation of the pharmacokinetic profile of means for valacyclovir, as measured in plasma samples of 30 subjects over a period of 24 hours.

[0319] The results collected in this study confirmed that the 90% confidence intervals for Test to Reference ratios of the geometric least squares means for AU o-t), AUC(o-oo), and Cmax acyclovir were within the standard bioequivalence acceptance range from 80.00 % to 125.00 % when administered under fasting conditions.

[0320] Similar relative bioavailability was demonstrated in this study, between a dose of 1000 mg of Test Valacyclovir oral suspension (5 ml of 200 mg / ml) and a 1000 mg ofan extemporaneous suspension (20 ml of 50 mg / ml) prepared from 500 mg Valtrex® tablets (Reference Product), administered under fasting conditions.

[0321] The 90% confidence intervals for Test under fed conditions (TFed; high-fat, high-calorie) to Test under fasting condition (Tfast) ratios of the geometric least squares means for AUC(o-t), AUC(o-co), and Cmax revealed that high-fat fed conditions increased the AUC but not Cmax of acyclovir relative to fasted conditions. However, the effect of food on the AUC of acyclovir was just slightly higher than the bioequivalence acceptance range (80-125%) which suggests there are no safety concerns.

[0322] Packaging and reconstitution of suspension from powder

[0323] Example 7

[0324] A storage container was selected for holding an amount of powder in a quantity that will allow multiple unit dosing upon reconstitution of the powder with water. The storage container can be a glass or plastic bottle. The desired amount was filled, and measurements were made. Two different strength powders were used: 50 mg / ml and 200 mg / ml valacyclovir powder. The selected bottle can hold 240 ml water. Measurements are summarized in Table 17. As can be seen from the table, the powders occupied less than half of the available fill volume (20 ml / 240 ml and 84 ml / 240 ml= 0,35)

[0325] Table 17: Multi-dose container with powder for reconstitution

[0326]

[0327] REFERENCES

[0328] 1. Highlights of prescribing information, Valtrex® (valacyclovir hydrochloride) Caplets, initial U.S. Approval: 1995 (Revised 11 / 2022).

[0329] 2. Pharmaceutical Compounding - nonsterile preparations 795, at https: / / doi.usp.org / USPNF / USPNF_M80140_01_01.html].3. Product Data Sheet - DuPont AmberLite IRP64 Ion Exchange Resin - Feb 2023.

[0330] 4. Bastiaans et al. (2016) A new paediatric formulation of valaciclovir: development and bioequivalence assessment. Arch dis Child October 2016 Vol 101 No 10, pages 971-972.

[0331] 5. Bastiaans et al. (2017) In vivo and in vitro palatability testing of a new paediatric formulation of valacyclovir. Br J Clin Pharmacol 83 2789-2797.

[0332] 6. Sharma (2014) Ion Exchange resins and their applications. J. Drug Delivery Ther., 4(4):115-123.

Claims

CLAIMS1. A valacyclovir resinate comprising crystalline valacyclovir hydrochloride hydrate (API) loaded onto a cationic ion exchange resin particle having carboxylic acid functional groups (IER), in a valacyclovir hydrochloride to IER weight-to-weight ratio of 1:0.4 to 1:0.6, wherein the chloride content is 9.0-11.0 % w / w on anhydrous and solvent-free basis with respect to API as determined by potentiometric titration; preferably the carboxylic acid functional groups are provided on a backbone of a methacrylic acid copolymer with divinyl benzene.

2. The valacyclovir resinate according to claim 1, wherein the water content is between 5 and 12% w / w, as determined by Karl Fisher water titration.

3. The valacyclovir resinate according to claim 1 or 2, wherein the valacyclovir hydrochloride hydrate is selected from monohydrate, dihydrate and sesqui hydrate.

4. The valacyclovir resinate according to claim 3, wherein the valacyclovir hydrochloride hydrate is the valacyclovir hydrochloride sesquihydrate (form I).

5. The valacyclovir resinate according to claim 4, comprising 2 theta characteristic peaks, measured by X-Ray Diffraction, as follows: 3.8°+ / -0.1, 8.7°+ / -0.1, 9.6°+ / -0.1, 10.7°+ / -0.1, 11.0°+ / -0.1, 13.5°+ / -0.2, 16.6°+ / -0.1, 20.3°+ / - 0.2, 21.6°+ / -0.2, 24.1°+ / -0.1.

6. The valacyclovir resinate according to any of claims 1 to 5, wherein the valacyclovir resinate was obtained from a process comprising the steps of: - dry blending of crystalline valacyclovir hydrochloride hydrate and cationic ion exchange resin particles, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups,- adding 10-30%, preferably 20%, water on solids content to the dry blend to obtain a premix,- wet granulating the premix to obtain crystalline valacyclovir hydrochloride hydrate loaded on the cationic ion exchange resin particles, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups,- drying the granules obtained to a water content below 12% w / w as determined by Karl Fisher water titration; wherein the granules are dried for at least 20 min at a temperature of 40-50°C, preferably 45°C;- wherein the process is devoid of a washing step.

7. The valacyclovir resinate according to claim 6, wherein the crystalline valacyclovir hydrochloride hydrate used in the dry blend has a water content of at least 4 % w / w.

8. A valacyclovir powder for the preparation of an orally administrable aqueous valacyclovir suspension, comprising: a valacyclovir resinate according to any of claims 1 to 7.

9. The valacyclovir powder according to claim 8, wherein the loaded porous ion exchange resin particle has a chloride ion content of 9.0-11.0 % w / w on anhydrous and solvent-free basis with respect to API as measured by potentiometric titration and the water content of the powder is 5-12% w / w as measured by Karl Fisher water titration.

10. The valacyclovir powder according to claim 8 or 9, wherein the valacyclovir hydrochloride is in sesquihydrate form (form I) and is characterized by an XRD spectrum with 2 theta characteristic peaks as follows: 3.6 + / -0.1, 8.6 + / - 0.2, 10.5 + / - 0.2, 10.9 + / -0.2, 21.4 + / - 0.2; 24.0 + / - 0.2; 26.7 + / -0.

2. and resin peak 14.0-15. l(halo) + / -0.2.

11. The valacyclovir powder according to any of claims 8 to 10, having a storage stability of at least 3 months, more preferably at least 6 months, most preferably of at least 12 months, measured at40°C and 75% Relative Humidity.

12. A method of manufacturing a valacyclovir powder according to any of claims 8 to 11, comprising the steps of:- dry blending of crystalline valacyclovir hydrochloride hydrate (API) and a cationic ion exchange resin particle, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups (IER) in a weight-to-weight valacyclovir hydrochloride to IER ratio of 1:0.4 to 1:0.6, preferably 1:0.5,- adding 10-30%, preferably 20%, water on solids content to the dry blend to obtain a premix,- wet granulating the premix to obtain crystalline valacyclovir hydrochloride hydrate loaded on the cationic ion exchange resin particle, preferably of methacrylic acid copolymer with divinyl benzene, having carboxylic acid functional groups,- drying the granules to a water content of at most 12% w / w as determined by Karl Fisher water titration, wherein the granules are dried for at least 20 min at a temperature of 40 to 50°C, preferably 45°C,- optionally milling the dried granules to a desired size,- adding dry pharmaceutically acceptable auxiliary ingredients, such as a suspending agent, to the (milled) granules thereby obtaining a powdered blend with a water content of at most 12% w / w, as determined by Karl Fisher water titration.

13. The method of manufacturing a valacyclovir powder according to claim 12, wherein the valacyclovir used is crystalline valacyclovir hydrochloride hydrate, form I, with a water content of 6 -11% w / w.

14. The method of manufacturing a valacyclovir powder according to claim 12 or 13, wherein the pharmaceutically acceptable auxiliary ingredients added include a glidant and a lubricant.

15. The method of manufacturing a valacyclovir powder according to any of claims 12 to 14, wherein multiple unit doses of the powdered blend are filled into a storage container, thereby occupying less than Vi of the fill volume of the storage container.

16. The method of manufacturing a valacyclovir powder according to claim 15, wherein the storage container is of plastic and after filling the plastic storage container with the powdered blend, the plastic storage container is sealed with a heat-sealable lid.

17. An orally administrable, aqueous, valacyclovir suspension, comprising:a pharmaceutically acceptable aqueous suspension base, anda valacyclovir resinate according to any of claims 1 to 7.18 The orally administrable, aqueous valacyclovir suspension according to claim 17, wherein the chloride ion content of the suspension is 9.0-11.0% w / w,preferably 9.2-10.2% w / w, on anhydrous and solvent-free basis with respect to API as measured by potentiometric titration.

19. The orally administrable, aqueous valacyclovir suspension according to claim 17 or 18, wherein the pH of the aqueous valacyclovir suspension is 2.5-3.5.

20. The orally administrable, aqueous valacyclovir suspension according to any of claims 17 to 19, wherein a minimum of 90 % of valacyclovir present in the suspension is loaded onto the ion exchange resin particles.

21. The orally administrable, aqueous valacyclovir suspension according to any of claims 17 to 20, wherein the suspension has an in-use storage stability of 45 days at room temperature (20 to 25°C) and refrigerated conditions (0°C-8°C).

22. The orally administrable valacyclovir aqueous suspension according to any of claims 17 to 21, wherein the valacyclovir suspension comprises 50 to 200 mg / ml valacyclovir (expressed in valacyclovir base equivalent).

23. The orally administrable aqueous valacyclovir suspension according to any of claims 17 to 22, wherein the aqueous valacyclovir suspension comprises 0.5 to 10 mg / ml suspending agent; preferably xanthan gum.

24. The orally administrable aqueous valacyclovir suspension according to any of claims 17 to 23, wherein the aqueous suspension comprises 0.1 to 10 mg / ml lubricant; preferably magnesium stearate.

25. The orally administrable aqueous valacyclovir suspension according to any of claims 17 to 24, comprising 1 to 10 mg / ml of one or more flavouring agents; preferably said one or more flavouring agents is banana flavour.

26. The orally administrable aqueous valacyclovir suspension according to any of claims 17 to 25, the liquid suspension having a white or off-white appearance.

27. The orally administrable aqueous valacyclovir suspension according to any of claims 17 to 26, wherein a single unit dose administration of 1000 mg valacyclovir (expressed as valacyclovir base equivalent) in the form of the valacyclovir suspension in a patient provides a bioequivalent pharmacokineticprofile for acyclovir by FDA requirements as compared to 1000 mg valacyclovir tablets (Reference Listed Drug).

28. The orally administrable aqueous valacyclovir suspension according to any of claims 17 to 27, wherein a single unit dose administration of 1000 mg valacyclovir (expressed as valacyclovir base equivalent) in the form of the valacyclovir suspension in a patient provides a pharmacokinetic profile for acyclovir as measured in blood plasma of 3950 ng / ml to 5000 ng / ml Cmax and 15900 ng.h / ml to 19550 ng.h / mL AUC(o-co).

29. The orally administrable aqueous valacyclovir suspension according to any of claims 17 to 28, for use in the treatment of a herpes virus infection in a patient in need thereof.

30. The orally administrable aqueous valacyclovir suspension for use according to claim 29, wherein the patient is administered 5 ml of the liquid suspension comprising 200 mg / ml valacyclovir (equivalents) or 20 ml of the liquid suspension comprising 50 mg / ml valacyclovir (equivalents).

31. The orally administrable aqueous valacyclovir suspension according to claim 27 or for use according to claim 30, wherein the patient is a paediatric patient.

32. The orally administrable aqueous valacyclovir suspension according to claim 31, wherein the flavouring agent is banana flavour.

33. A storage container provided for holding multiple unit doses of a powder for oral suspension, the container comprising:a valacyclovir powder according to any of claims 8 to 11 in an amount for multiple unit dosing,wherein the amount for multiple unit dosing is 1 to 50 g, andthe powder occupies at most 1 / 2 of the fill volume of the storage container, thereby providing for the addition of a pharmaceutically acceptable liquid suspension base for the preparation of the oral suspension in the storage container.

34. A kit of parts comprising the storage container according to claim 33, an oral dosing syringe, a bottle adaptor for holding the container and the dosing syringe, and a leaflet with instructions for storage and use of the kit.

35. The kit according to claim 34, wherein the kit is for use three times daily during a period of 5 days.

36. The kit according to claim 34 or 35, wherein instructions for storage include storage at room temperature (20°C to 25°C [68°F to 77°F]) for up to 45 days once the oral suspension is prepared.

37. A method of manufacturing multiple unit doses of an orally administrable liquid valacyclovir suspension, comprising the steps of:providing a storage container provided for holding multiple unit doses of a powder for oral suspension according to claim 33, the container comprising:a valacyclovir powder according to any of claims 8 to 11 in an amount for multiple unit dosing,wherein the amount for multiple unit dosing is 1 to 50 g, andthe powder occupies at most 1 / 2 of the fill volume of the storage container, - adding a pre-determined volume of a pharmaceutically acceptable liquid suspension base in a volume for suspension of the valacyclovir powder, preferably water, to the storage container thereby obtaining the multiple unit doses of the orally administrable liquid suspension.

38. The method of manufacturing an orally administrable liquid suspension according to claim 37, wherein the suspension comprises 50 to 200 mg valacyclovir / ml.

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