WO2021161317A1

WO2021161317A1 - Stable pharmaceutical compositions comprising valgancyclovir and uses thereof

Info

Publication number: WO2021161317A1
Application number: PCT/IL2021/050169
Authority: WO
Inventors: Lina SHPIRT IANKU; Yulia OSTROVSKY; Dmitry HAIKIN; Dafna Arieli
Original assignee: Cts Chemical Industries Ltd.
Priority date: 2020-02-12
Filing date: 2021-02-11
Publication date: 2021-08-19

Abstract

Stable pharmaceutical dosage forms comprising Valganciclovir or pharmaceutically acceptable salts thereof and certain organic acids, and their uses for treatment, prevention and maintenance of CMV-associated conditions are provided.

Description

STABLE PHARMACEUTICAL COMPOSITIONS COMPRISING VALGANCYCLOVIR

AND USES THEREOF

FIELD OF THE INVENTION The invention relates to stable pharmaceutical compositions comprising valganciclovir and their use in prevention, treatment and maintenance of conditions associated with Cytomegalovirus. BACKGROUND OF THE INVENTION

Cytomegalovirus (CMV) infection causes morbidity in solid organ transplant (SOT) recipients, either by direct injury or in association with chronic allograft rejection or other opportunistic infections. Ganciclovir is the treatment of choice, but this agent requires intravenous administration, which affects its feasibility for long-term use. Valganciclovir, which has an oral bioavailability of 60%, has proven to be useful for prophylaxis of CMV infection in high- risk SOT recipients and for treating retinitis in persons with acquired immunodeficiency syndrome.Valganciclovir is a prodrug which is the L-valyl ester of ganciclovir. It exists as a mixture of two diastereoisomers and when administered orally, both of these diastereoisomers rapidly turn into ganciclovir. Ganciclovir is a synthetic analogue of guanine. The advantage of valganciclovir is that it shows a similar effect in vivo to that of the ganciclovir given by intravenous route, while it is more effective than ganciclovir capsules when it comes to oral administration .

Valganciclovir hydrochloride is commercially available under the trade name Valcyte® in tablet form or powder form for oral solution. Valganciclovir hydrochloride is freely soluble under acidic conditions and has maximum stability at a pH below 3.8. Short-term stability data has shown that liquid dosage forms are unstable for the anticipated shelf life of the product. Therefore, developing solid pharmaceutical dosage forms of Valganciclovir or pharmaceutically acceptable salts of Valganciclovir for oral administration with improved stability and shelf-life remains an unmet medical need.

SUMMARY OF THE INVENTION

It is a principal object of the present invention to provide stable pharmaceutical dosage forms comprising Valganciclovir or a pharmaceutically acceptable salt thereof.

The invention provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid.

The invention further provides a dry powder for solution comprising Valganciclovir or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable carrier, and at least one organic acid selected from the group consisting of DL-malic acid, maleic acid, and malonic acid.

The invention further provides a method of treating a human subject afflicted with a disorder associated with Cytomegalovirus comprising administering to the subject an amount of a pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid; wherein said amount is effective to treat the human subject.

The invention further provides a method for preventing a CMV disease in a human subject in need comprising administering to said subject an effective amount of pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid. The invention further provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, for use as a medicament. The invention further provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, for treating a disorder associated with Cytomegalovirus.

The invention further provides use of a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, in a manufacture of a medicament for treating a disorder associated with Cytomegalovirus.

The invention further provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, for preventing a disorder associated with Cytomegalovirus.

The invention further provides use a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, in a manufacture of a medicament for preventing a disorder associated with Cytomegalovirus.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is now described more fully hereinafter with reference to the accompanying examples, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art.

According to some embodiments, the invention provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid. In one embodiment, the dosage form upon storage of two weeks under the conditions of 25°C and 60%RH has Ganciclovir content of less than 1.1%. In one embodiment, dosage form upon storage of two weeks under the conditions of 25°C and 60%RH has Ganciclovir content of 1.1%, 1.05%, 1.0%,

0.95%, 0.9%, 0.85%, 0.8%, 0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, 0.05% or below. In another embodiment, the dosage form upon storage of one month under the conditions of 25°C and 60%RH has Ganciclovir content of less than 1.5%. In one embodiment, the dosage form upon storage of one month under the conditions of 25°C and 60%RH has Ganciclovir content of 1.5%, 1.45%, 1.4%, 1.35%, 1.3, 1.25%, 1.2%, 1.15%, 1.1%, 1.05%, 1.0%, 0.95%, 0.9%, 0.85%, 0.8%, 0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%,

0.2%, 0.15%, 0.1%, 0.05% or below. In one embodiment, the dosage form upon storage of two months under the conditions of 25°C and 60%RH has Ganciclovir content of less than 2.3%. In one embodiment, the dosage form upon storage of two months under the conditions of 25°C and 60%RH has Ganciclovir content of 2.3%, 2.25%, 2.2%, 2.15%, 2.1%, 2.05%, 2.0%, 1.95%, 1.9%, 1.85%, 1.8%, 1.75%, 1.7%, 1.65%, 1.6%, 1.55%, 1.5%, 1.45%, 1.4%, 1.35%, 1.3, 1.25%, 1.2%, 1.15%, 1.1%, 1.05%, 1.0%, 0.95%, 0.9%, 0.85%, 0.8%,

0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, 0.05% or below. In yet another embodiment, the dosage form upon storage of one month under the conditions of 2-8°C has Ganciclovir content of less than 0.8%. In one embodiment, the dosage form upon storage of one month under the conditions of 2-8°C has Ganciclovir content of 0.8%, 0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%,

0.25%, 0.2%, 0.15%, 0.1%, 0.05% or below. In one embodiment, the dosage form upon storage of two months under the conditions of 2-8°C, has Ganciclovir content of less than 0.9%. In one embodiment, the dosage form upon storage of two months under the conditions of 2-8°C, has Ganciclovir content of 0.9%, 0.85%,

0.8%, 0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, 0.05% or below. According to some embodiments, the pharmaceutical dosage form is a liquid dosage form. According to some embodiments, Valganciclovir or a salt thereof is in an amount equivalent to 50 mg/ml of Valganciclovir base. According to some embodiments, the organic acid in the pharmaceutical dosage form is DL-malic acid. In one embodiment, the concentration of DL-malic acid in the pharmaceutical dosage form is about 4 mg/ml. In one embodiment, the concentration of DL-malic acid in the pharmaceutical dosage form is from 3.4mg/ml to 4.7 mg/ml. According to some embodiments, the organic acid in the pharmaceutical dosage form is malonic acid. In one embodiment, the concentration of malonic acid in the pharmaceutical dosage form is about 1.6 mg/ml. In one embodiment, the amount of malonic acid in the pharmaceutical dosage form is from 1.3mg/ml to 1.9mg/ml. According to some embodiments, the organic acid in the pharmaceutical dosage form is maleic acid. In one embodiment, the concentration of maleic acid in the pharmaceutical dosage form is about 1 mg/ml. In one embodiment, the amount of maleic acid in the pharmaceutical dosage form is from 0.8mg/ml to 1.2mg/ml. According to some embodiments, the dosage form is a liquid dosage form reconstituted from a dry powder for solution. According to some embodiments, the pharmaceutical dosage form further comprises at least one pharmaceutically acceptable carrier. According to some embodiments, the pharmaceutical dosage form further comprises at least one flavoring agent. According to some embodiments, the invention provides a dry powder for solution comprising Valganciclovir hydrochloride, at least one pharmaceutically acceptable carrier, and at least one organic acid selected from the group consisting of DL-malic acid, maleic acid, and malonic acid. According to some embodiments, the invention provides a solution comprising Valganciclovir reconstituted from the dry powder. According to some embodiments, the invention provides a method of treating a human subject afflicted with a disorder associated with Cytomegalovirus (CMVj comprising administering to the subject an amount of the pharmaceutical dosage comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid. In one embodiment, the organic acid is DL-malic acid. In another embodiment, the organic acid is maleic acid. In yet another embodiment, the organic acid is malonic acid. In one embodiment, the disorder associated with the CMV is CMV-retinitis. In one embodiment, the human subject is at the age of 12 or below. In another embodiment, the human subject is above the age of 12. In one embodiment, the human subject is afflicted with acquired immunodeficiency syndrome (AIDS). In one embodiment, the method comprises induction and maintenance treatment of CMV-retinitis. According to some embodiments, provided a method for preventing a CMV disease in a human subject in need comprising administering to said subject an effective amount of pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid. In one embodiment, the organic acid is DL-malic acid. In another embodiment, the organic acid is maleic acid. In yet another embodiment, the organic acid is malonic acid. According to some embodiments, the human subject in need received a solid organ transplant from a CMV-positive donor prior to the administration of the pharmaceutical dosage form. In one embodiment, prior to the administration of the pharmaceutical dosage form the human subject had CMV-negative blood test result. In the context of the invention, the phrase "CMV-negative blood test result" refers, without limitation, to a situation when no antibodies to CMV in the blood sample taken from the human subject were detected by the commonly used, state of the art, laboratory equipment. In one embodiment, the age of the human subject is 18 years and below. In another embodiment, the age of the human subject is 19 and above. According to some embodiments, provided a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid for use as a medicament. In one embodiment, the organic acid is DL-malic acid. In another embodiment, the organic acid is maleic acid. In yet another embodiment, the organic acid is malonic acid. According to some embodiments, the invention provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, for treating a disorder associated with CMV. In one embodiment, the organic acid is DL-malic acid. In another embodiment, the organic acid is maleic acid. In yet another embodiment, the organic acid is malonic acid. According to some embodiments, the invention provides use of a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, in a manufacture of a medicament for treating a disorder associated with CMV. In one embodiment, the organic acid is DL-malic acid. In another embodiment, the organic acid is maleic acid. In yet another embodiment, the organic acid is malonic acid. According to some embodiments, provided a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, for preventing a disorder associated with CMV. In one embodiment, the organic acid is DL-malic acid. In another embodiment, the organic acid is maleic acid. In yet another embodiment, the organic acid is malonic acid. According to some embodiments, provided use of stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid, in a manufacture of a medicament for preventing a disorder associated with CMV. In one embodiment, the organic acid is DL-malic acid. In another embodiment, the organic acid is maleic acid. In yet another embodiment, the organic acid is malonic acid. According to some embodiments, the invention provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and succinic acid. In one embodiment, the concentration of succinic acid in the pharmaceutical dosage form is about 11.7 mg/ml. In another embodiment, the concentration of succinic acid in the pharmaceutical dosage form is from 9.4 mg/ml to 14.0 mg/ml. In one embodiment, the dosage form comprising the succinic acid upon storage of one month under the conditions of 25°C and 60%RH has Ganciclovir content of less 1.7%. In one embodiment, the dosage form comprising the succinic acid upon storage of two months under the conditions of 25°C and 60%RH has Ganciclovir content of less than 2.95%. According to some embodiments, the invention provides a method of treating a human subject afflicted with a disorder associated with Cytomegalovirus comprising administering to the subject an amount of the pharmaceutical dosage form comprising

Valganciclovir or a pharmaceutically acceptable salt thereof, and succinic acid. According to some embodiments, the invention provides a method of preventing a disorder associated with Cytomegalovirus comprising administering to the subject an amount of the pharmaceutical dosage form comprising

Valganciclovir or a pharmaceutically acceptable salt thereof, and succinic acid. According to some embodiments, the invention provides a stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and succinic acid for use as a medicament.

Example 1: Preparation of experimental batches containing potential stabilizing acids.

Preparation of Placebo stock

Placebo stock solution was prepared by adding Povidone K-25, sodium benzoate, sodium saccharin and D-mannitol to 1500 gr of purified water and mixing for lh until fully dissolved. The composition of the placebo stock is detailed in Table l.

Table 1 : Composition of placebo stock solution

Preparation of experimental batches

Four developmental batches containing Valganciclovir (as powder API) and different acids were prepared as follows: 162.2g of placebo stock solution were weighed into a measuring beaker. The pH was adjusted to pH= 2.9-3.1 using different type of acid for each batch. The pH range was set according to the pH of the reference product Valcyte® 50mg/ml powder for oral solution after re-constitution (pH= 3.04). Valganciclovir (as Hydrochloride) was added to each measuring beaker and mixed until fully dissolved. Each measuring beaker was filled to 200ml volume using purified water and mixed for lOmin. pH was measured. Each batch was filled into 15ml amber bottles for stability studies, filling volume: 15ml. The type and amount of each acid used, and the final pH values are detailed in Table 2.

Table 2 : Description of developmental batches.

¹55.15 mg/ml of Valganciclovir Hydrochloride are Equivalent to 50mg/ml of Valganciclovir

Preparation of reference product Valcyte®50mg/ml solution

Solution of the reference product Valcyte ® was prepared by adding 91ml of purified water to 12g of powder and mixing, as required in the product prescribing information. The prepared solution was filled into 15ml amber bottles for stability studies, filling volume: 10ml.

Initial stability studies

Stability conditions and sampling points of the stability studies conducted on the developmental batches and reference product are summarized in Table 3.

Table3 : Stability conditions and sampling points

¹ To was tested only for Valcyte® reference product. To for developmental batches was considered as the raw material (active ingredient) results.

Example 2: stability study on the experimental batches under the conditions of 25°C/60%RH. summarize the results of stability

studies on experimental batches 1-4 at 25°C/60%RH.

Table 4 : Stability results 2 weeks, at 25°C/60%RH

Table 5: Stability results 1 month, at 25°C/60%RH

Table 6: Stability results 2 months, at 25°C/60%RH Example 3: stability study on the experimental batches under the conditions of 2-8°C.

Tables 7-9 summarize the results of stability studies on experimental batches 1-4 at 2-8°C.

Table 7: Stability results, Time⁰, at 2-8°C

Table 8: Stability results, 1 month, at 2-8°C

Table 9: Stability results, 2 months, at 2-8°C

Table 10 provides Ganciclovir concentration summary of the stability studies on experimental batches under different conditions and 2 months sampling point.

Table 10: Ganciclovir concentration summary.

Discussion

Based on the package leaflet of Valcyte® the solution is stable at the refrigerator (2-8°C) for 49 days from the day of preparation. The main impurity detected during stability in both experimental batches as well as the reference product, is the active metabolite, Ganciclovir. The reference product solution shows 1.5% increase in Ganciclovir level after 2 months at 25°C/60%RH, while only minor increase (0.1%) is seen under the recommended storage conditions 2-8°C. Experimental batches showed an increase of 1.4-2.2% after 2 months at accelerated conditions with (clear) preference for malonic acid as stabilizer (lowest increase of 1.4%). A similar level of about 0.8% Ganciclovir (0.2-0.3% increase) was found in all experimental batches stored for 2 months under the recommended storage conditions of 2-8°C.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a," "an" and "the" are intended to include plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" or "comprising, " when used in this specification, specify the presence of stated features, integers, steps, operations, elements components and/or groups or combinations thereof, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components and/or groups or combinations thereof. As used herein the terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to". The term "consisting of" means "including and limited to".

As used herein, the term "and/or" includes any and all possible combinations or one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and claims and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.

It will be understood that, although the terms first, second, etc., may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. Rather, these terms are only used to distinguish one element, component, region, layer and/or section, from another element, component, region, layer and/or section.

Certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements .

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

Whenever the term "about" is used, it is meant to refer to a measurable value such as an amount, a temporal duration, and the like, and is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

As used herein the term "patient" or "subject" is meant to include any mammal. A "mammal," as used herein, refers to any animal classified as a mammal, including but not limited to, humans, experimental animals including monkeys, rats, mice, and guinea pigs, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like. As used herein, a "pharmaceutically acceptable" carrier or excipient is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. "Treating" or "treatment" of a disease as used herein includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e • I arresting or reducing the development of the disease or its clinical symptoms, or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A "therapeutically-effective amount" or an "effective amount" means the amount of a compound or a dosage form that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically- effective amount" will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. As used herein the term "Pharmaceutically-acceptable salt" refers to salts which retain the biological effectiveness and properties of compounds which are not biologically or otherwise undesirable . Pharmaceutically acceptable salts refer to pharmaceutically acceptable salts of the compounds, which salts are derived from a variety of organic and inorganic counter ions well known in the art.

The pharmaceutical dosage forms may be prepared as medicaments to be administered orally. Suitable forms for oral administration include, without limitation, solutions, syrups and suspensions; such as ready-to-use syrups and suspensions, or reconstituted from solid dosage form such as, without limitation, dry powder. The dosage form may contain suitable binders, lubricants, coloring agents, flavoring agents, flow- inducing agents, stabilizing agents, solubilizing agents, antioxidants, buffering agent, chelating agents, and fillers, all collectively or individually fall under the definition of the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient". For oral administration in the dosage form, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert filler such as gelatin, agar, starch, methyl cellulose, mannitol, xylitol, sorbitol, maltodextrin and the like. Suitable binders include starch, gelatin, natural sugars such as corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, cellulose based soluble polymers such as but not limited to hydroxypropylomethylcellulose, hydroxypropylcellulose, polyethylene glycol, and the like. Glidants used in these dosage forms include sodium benzoate, sodium acetate, polyethylene glycole, and the like. Stabilizing (antimicrobial) agents include benzoic acid, and salts thereof, parahydroxybenzoate and salts thereof, sorbic acid and salts thereof and the like. Stabilizing (physical) agents include viscosity enhancing polymers such as hydroxyethyl cellulose, xanthan gum and the like.

Claims

1. A stable pharmaceutical dosage form comprising Valganciclovir or a pharmaceutically acceptable salt thereof, and at least one organic acid selected from the group consisting of maleic acid, malonic acid, and malic acid.

2. The pharmaceutical dosage form of claim 1, wherein the dosage form upon storage of two weeks under the conditions of 25°C and 60%RH has Ganciclovir content of less than 1.1%.

3. The pharmaceutical dosage form of claim 1 or 2, wherein the dosage form upon storage of one month under the conditions of 25°C and 60%RH has Ganciclovir content of less than 1.5%.

4. The pharmaceutical dosage form of any one of claims 1 to 3, wherein the dosage form upon storage of two months under the conditions of 25°C and 60%RH has Ganciclovir content of less than 2.3%.

5. The pharmaceutical dosage form of any one of claims 1 to 4, wherein the dosage form upon storage of one month under the conditions of 2-8°C has Ganciclovir content of less than

0.8%.

6. The pharmaceutical dosage form of any one of claims 1 to 5, wherein the dosage form upon storage of two months under the conditions of 2-8°C, has Ganciclovir content of less than

0.9%.

7. The pharmaceutical dosage form of any one of claims 1 to 6, wherein the dosage form is a liquid dosage form.

8. The pharmaceutical dosage form of any one of claims 1 to 7, comprising Valganciclovir or a salt thereof in an amount equivalent to 50 mg/ml of Valganciclovir base.

9. The pharmaceutical dosage form of any one of claims 1 to 8, wherein the organic acid is DL-malic acid.

10. The pharmaceutical dosage form of claim 9, wherein the concentration of DL-malic acid in the pharmaceutical dosage form is about 4 mg/ml.

11. The pharmaceutical dosage form of claim 9, wherein the concentration of DL-malic acid in the pharmaceutical dosage form is from 3.4mg/ml to 4.7 mg/ml

12. The pharmaceutical dosage form of any one of claims 1 to 8, wherein the organic acid is malonic acid

13. The pharmaceutical dosage form of claim 12, wherein the concentration of malonic acid in the pharmaceutical dosage form is about 1.6 mg/ml.

14. The pharmaceutical dosage form of claim 12, wherein the amount of malonic acid in the pharmaceutical dosage form is from 1.3mg/ml to 1.9mg/ml.

15. The pharmaceutical dosage form of any one of claims 1 to 8, wherein the organic acid is maleic acid.

16. The pharmaceutical dosage form of claim 15, wherein the concentration of maleic acid in the pharmaceutical dosage form is about 1 mg/ml.

17. The pharmaceutical dosage form of claim 15, wherein the concentration of maleic acid in the pharmaceutical dosage form is from 0.8mg/ml to 1.2mg/ml.

18. The pharmaceutical dosage form of any one of claims 1 to 17, wherein the dosage form is a liquid dosage form reconstituted from a dry powder for solution.

19. The pharmaceutical dosage form of any one of claims 1 to 18, further comprising at least one pharmaceutically acceptable carrier.

20. The pharmaceutical dosage form of any one of claims 1 to 19, further comprising a flavoring agent.

21. A dry powder for solution comprising Valganciclovir or pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable carrier, and at least one organic acid selected from the group consisting of DL-malic acid, maleic acid, and malonic acid.

22. A solution comprising Valganciclovir or pharmaceutically acceptable salt thereof, reconstituted from the dry powder of claim 21.

23. A method of treating a human subject afflicted with a disorder associated with Cytomegalovirus, comprising administering to the subject an amount of the pharmaceutical dosage form of anyone of claims 1 to 20, effective to treat the human subject.

24. The method of claim 23, wherein the disorder associated with Cytomegalovirus is cytomegalovirus (CMVj retinitis.

25. The method of claim 23 or 24, wherein the human subject is at the age of 12 or below.

26. The method of claim 23 or 24, wherein the human subject is above the age of 12.

27. The method of any one of claims 23 to 26, wherein the human subject is afflicted with acquired immunodeficiency syndrome (AIDS).

28. The method of any one of claims 24 to 27, comprising induction and maintenance treatment of cytomegalovirus (CMVj retinitis.

29. A method for preventing a CMV disease in a human subject in need comprising administering to said subject an effective amount of pharmaceutical dosage form of any one of claims 1 to 20.

30. The method of claim 29, wherein the human subject in need received a solid organ transplant from a CMV-positive donor prior to the administration of the pharmaceutical dosage form.

31. The method of claim 29 or 30, wherein prior to the administration of the pharmaceutical dosage form the human subject had CMV-negative blood test result.

32. The method of any one of claims 29 to 31, wherein the age of the human subject is 18 years and below.

33. The method of any one of claims 29 to 31, wherein the age of the human subject is 19 and above.

34. A stable pharmaceutical dosage form of any one of claims 1 to 20 for use as a medicament.

35. A stable pharmaceutical dosage form of any one of claims 1 to 20 for treating a disorder associated with Cytomegalovirus.

36. Use of stable pharmaceutical dosage form of any one of claims 1 to 20 in a manufacture of a medicament for treating a disorder associated with Cytomegalovirus.

37. The stable pharmaceutical dosage form of any one of claims 1 to 20 for preventing a disorder associated with Cytomegalovirus.

38. Use of stable pharmaceutical dosage form of any one of claims 1 to 20 in a manufacture of a medicament for preventing a disorder associated with Cytomegalovirus.