PEDIATRIC POWDER FOR ORAL SUSPENSION CONTAINING ANTIVIRAL AGENT AND METHOD FOR THE PREPARATION THEREOF

Abstract

A process for preparing a powder for reconstitution as a suspension includes the following steps: First, complexing Valaciclovir with an ion exchange resin and forming Drug-Resin complex (DRC) particles. The complexing includes Dry blending of Drug:Ion Exchange Resin in a ratio 1:0.8 to form a blend; Kneading the blend with water in a ratio of Drug:Ion Exchange Resin:Water 1:0.8:0.5 to form a wet mass; Drying of the wet mass at 40° C.
Next, milling of the Drug-Resin complex particles until particle size gets less than 250 μm, and then dry mixing of the Drug-Resin complex particles with excipients to form an internal phase. The excipients of the internal phase comprise a suspending agent and a pH agent, and the suspending agent forms a film around each DRC particle and the film decreases interparticle attraction. Next, mixing the internal phase with excipients of an external phase to form the powder, and then sifting the powder to eliminate any clumps.

Claims

1. A process for preparing a powder for reconstitution as a suspension, wherein the powder comprises Valaciclovir or pharmaceutical acceptable salt or derivative thereof and an ion exchange resin, the process comprising the following steps: (a) Complexing Valaciclovir with the ion exchange resin and forming Drug-Resin complex (DRC) particles, wherein each DRC particle comprises hydrogen bonds between the ion exchange resin and a cationic center of Valaciclovir, and wherein the ratio of Valaciclovir to the ion exchange resin within the DRC particle is 1:0.8 and wherein said complexing comprises: Dry blending of Drug:Ion Exchange Resin in a ratio 1:0.8 to form a blend; Kneading the blend with water in a ratio of Drug:Ion Exchange Resin:Water 1:0.8:0.5 to form a wet mass; Drying of the wet mass at 40° C.; (b) Milling of the Drug-Resin complex particles until particle size gets less than 250 μm; (c) Dry mixing of the Drug-Resin complex particles with excipients to form an internal phase, wherein the excipients of the internal phase comprise a suspending agent and a pH agent, and wherein the suspending agent forms a film around each DRC particle and the film decreases interparticle attraction; (d) Mixing the internal phase with excipients of an external phase to form the powder; and (e) Sifting the powder to eliminate any clumps.

2. The process of claim 1, further comprising reconstituting the powder with an aqueous diluent as suspension for oral administration.

3. The process of claim 1, further comprising suspending the powder in 900 ml HCl 0.1N and releasing more than 95% of Valaciclovir from complexation with the ion exchange resin within 10 minutes.

4. The process of claim 1, wherein the ion exchange resin is a cationic acid ion exchange resin.

5. The process of claim 1, wherein the ion exchange resin comprises a cross linked acrylic co-polymer matrix and the ion exchange resin is marketed as Indion™ 204.

6. The process of claim 1, wherein the suspending agent is xanthan gum and the pH agent is selected from sodium hydroxide or tri-sodium citrate dihydrate.

7. The process of claim 1, wherein the ratio of the suspending agent to the pH agent is in the range of 0.069 to 0.37.

8. The process of claim 1, wherein the excipients of the external phase comprise flavoring agents.

9. The process of claim 1, wherein the ion exchange resin comprises a weak cation acid ion exchange resin or a strong cation acid ion exchange resin.

10. The process of claim 1, wherein the powder for reconstitution as suspension is appropriate for children from birth through 18 years of age.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0026] For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.

[0027] As already mentioned the main object of the present invention is to provide a stable pharmaceutical composition of Valaciclovir or pharmaceutical acceptable salt or derivative thereof for oral administration appropriate for children.

[0028] Because of physiological and pharmacokinetic differences between the adult and pediatric population there is the need for the development of formulations specifically studied and designed for children. In children gastric emptying time and gastric pH is variable, and there are differences in the surface area of the absorptive sites and gastrointestinal permeability. There are also reported changes in the biliary function depending upon age, body water and adipose tissue, which may lead to differences in drug disposition and elimination. In most cases, a child's dose is calculated based on the body weight, whereas a few cases based on body surface are also in use.

[0029] An ideal formulation for children will allow minimal dosage and frequency; will have minimal impact on lifestyle; a minimum of nontoxic excipients and will have convenient, easy and reliable administration.

[0030] Children are a very heterogeneous population that includes newborns, infants, toddlers, pre-schoolers, school-age children and adolescents. Therefore, there is the need to develop formulations appropriate for all the pediatric subpopulations that will use the products. Liquid formulations (solutions, suspensions, syrups, etc) have been popular because of the ease of administering them to children of different ages and the ease of dosing more precisely according to body weight or body surface area. Liquid medicines for oral administration are usually recommended for infants and younger children so the ability to mask unpleasant taste is crucial.

[0031] The present invention proposes a palatable powder that is reconstituted in a suspension for children from birth through 18 years of age. Therefore, the proposed invention covers children of all ages and all children can be dosed on the same manner, i.e. on a ‘per Kg’ basis. Without being limited volumes to be administered for varicella indication (dose: 20 mg/kg) and herpes labialis indication (dose: 30 mg/kg) depend on strength and child's weight.

[0032] The main advantage of the powder to be reconstituted in a suspension instead of a ready-made liquid formulation of Valaciclovir is the favourable stability of the product throughout its self-life, as stability problems have been reported when Valacyclovir is formulated as a ready-made liquid.

[0033] The most important problem encountered at the development of Valaciclovir formulations of the present invention was the extremely bitter taste of active ingredient. Taste is an important parameter in administering drugs orally. In paediatric patients, acceptance of a dosage form is primarily dependent on a child's taste preference. Different taste masking technologies have been used to address the problem of patient compliance. Taste masking of water soluble bitter drugs, especially those with a high dose, is difficult to achieve by using sweeteners alone. As a consequence, more efficient techniques such as coating, microencapsulation and granulation have been used in combination with the sweeteners.

[0034] The powder for oral suspension proposed by the present invention comprises a complex of Valaciclovir with an ion exchange resin in a specific ratio in order to obtain a palatable and child-friendly product.

[0035] The powder for oral suspension of the present invention may also contain suspending agents and pH agents.

[0036] Suspending agents form films around particles and decrease interparticle attraction. Suspending agents also act as thickening agents. They increase the viscosity of the solution, which is necessary to prevent sedimentation of the suspended particles as per Stokes' law. Property of a well formulated suspension is that it can be easily re-suspended by the use of moderate agitation.

[0037] Suspending agents may be selected from alginates, acacia, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, xanthan gum, tragacanth. The preferred compositions of the present invention comprise preferably xanthan gum.

[0038] PH agents are additives used to control pH. They may be selected from hydrochloric acid, sodium hydroxide, sodium hydrogen sulphate, tri-sodium citrate dihydrate. The preferred compositions of the present invention comprise preferably sodium hydroxide or tri-sodium citrate dihydrate.

[0039] Ion exchange Resins (IER) were extensively used in the development of formulations of the present invention as taste masking agents. IERs are solid and suitably insoluble high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium. The resulting ion exchange is reversible and stoichiometric with the displacement of one ionic species by another. Research over the last few years has revealed that IERs are equally suitable for drug delivery technologies, including controlled release, transdermal, nasal, topical and taste masking. Being high molecular weight water insoluble polymers, the resins are not absorbed by the body and are therefore inert.

[0040] Since most drugs possess ionic sites in their molecule, the resin's charge provides a means to loosely bind such drugs and this complex prevents the drug release in the saliva, thus resulting in taste masking. The nature of the drug resin complex formed is such that the average pH of 6.7 and cation concentration of about 40 meq/L in the saliva are not able to break the drug resin complex but it is weak enough to be broken down by hydrochloric acid present in the stomach. Thus, the drug resin complex is absolutely tasteless with no after taste, and at the same time, its bioavailability is not affected.

[0041] A critical factor to prepare a Drug-Resin complex (DRC) was the choice of the right IER. Valaciclovir.HCl contains an exchangeable secondary amine moiety i.e. cationic center. Therefore, cation exchange resins are highly recommended for the complex formation. Weak cation acid ion exchange resins such as Indion™ 204, Indion™ 214 as well as a strong cation acid resin such as Purolite™ C100CaMR were tested in order to form the DRC.

[0042] Mediums of different pH were examined in order to achieve the maximum drug loading into the resin. For this reason, the pH of solutions was adjusted at 3, 4, 5, 6, and 7. The drug loaded was evaluated spectrophotometrically. The % w/w unbound drug for pH 3, 4, 5, 6, 7 and water was found to be 79.85%±2.19%, 75.24%±2.91%, 66.69%±2.76%, 61.19%±2.61%, 30.91%±2.53% and 72.61%±2.81% respectively. Buffer pH=7 enhanced more the effect of drug loading.

[0043] The next step was to examine the effect of drug loading into the resin for buffer pH=7 of different ion strength. For this reason, buffer pH=7 of normality 0.1N, 0.2N, 1N were prepared and the drug loaded was evaluated spectrophotometrically as before. Buffer pH=7 0.2N was the most suitable medium as the higher drug loading was reached. (61.60%±2.05%).

[0044] At this point of studies, the research focused on the type of IER. For this reason, resins of different functional group were examined to reach the higher drug loading. The % w/w unbound drug for Indion™ 204, Indion™ 214, Kyron™ T-134, Kyron™ T-314, Purolite™ C115KMR and Purolite™ C100CaMR was found to be 30.91%±1.97%, 44%±2.95%, 59.95%±2.96%, 87.99%±1.67%, 58.42%±2.93% and 21.80%±1.29% respectively. As a result, Purolite™ C100CaMR and Indion™ 204 were the most preferred resins that could form hydrogen bonds with the cationic center of Valaciclovir and prevent the release in saliva.

[0045] Another important factor that was examined was the quantity of water used for the preparation of the drug-resin complex. The wet granulation method was selected for the DRC preparation as it could perform a stable, easy-to use complex with a neutral taste. It was observed that excessive amounts of water led to a DRC that didn't release the drug even in the stomach environment. DRCs of different Drug:Resin:Water ratio were tested in order to determine the appropriate water quantity. Optimum dissolution profile was achieved when Drug:Resin in the ratio 1:0.8 was granulated with water according to ratio Drug:Resin:Water 1:0.8:0.5.

[0046] The extremely bitter taste of Valaciclovir was the main problem of the development. Ion exchange resins prepared a Drug:Resin complex with neutral taste that didn't sustain the drug release. Indion™ 204, a weak cation resin, not only appeared as the most desirable taste masking agent but also, it didn't affect significantly the drug degradation effect. The complex was weak enough to be broken down by the hydrochloric acid (simulated stomach fluids). Different API:resin ratios were evaluated within the context of current invention to figure out the impact of resin on finished product oral suspension quality. It was noticed that formulation Trials with API:Resin ratio 1:0.4 up to 1:1 exhibit a stable profile under both long-term & accelerated storage conditions as well as stressing conditions. Moreover, the palatability and appearance of oral suspension was also acceptable. Thus, any API:resin ratio within the current range is considered suitable for current finished product.

[0047] It is possible to prepare dosage forms of different strength using appropriate quantity of the same composition, thereby limiting the cost of production and minimizing the number, and consequently the cost of clinical studies required for the approval of the product by the authorities.

[0048] The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:

EXAMPLES

[0049] Both Indion™ 204 and Purolite™ C100CaMR were evaluated for their taste/feel acceptability and drug contamination status. Formulations 1 to 3 of Drug:Resin 1:1, 1:0.8, 1:0.5 respectively were prepared for both resins and the palatability was estimated by a three person panel. For each Formulation 1 to 3 a composition without resin was also examined in order to assess the impact of resins as taste masking agents. (Table 1). The process chosen for the preparation of Formulations 1 to 3 was wet and dry mixing following the below steps: [0050] Dry blending of Drug:Resin; [0051] Kneading the above blend with water; [0052] Drying of the wet mass at 40° C.; [0053] Milling of DRC until particle size gets less than 250 μm; [0054] Dry mixing of the DRC and the excipients of the internal phase; [0055] Mixing with the excipients of the external phase; [0056] Shifting the powder to eliminate any clumps; [0057] Reconstitution of powder with suitable aqueous diluent.

TABLE-US-00001 TABLE 1 Formulations 1 to 3 Drug:Resin 1:1 1:0.8 1:0.5 Formulation 1 Formulation 2 Formulation 3 Ingredients mg/ml Internal phase Valaciclovir 50.000 50.000 50.000 50.000 50.000 50.000 Valaciclovir 56.180 56.180 56.180 56.180 56.180 56.180 HCl hydrated IER 50.000 — 40.000 — 25.000 — Xanthan gum 4.167 4.167 4.167 4.167 2.083 2.083 Microcrystalline 8.333 8.333 8.333 8.333 8.333 8.333 cellulose Sucralose 1.667 1.667 1.667 1.667 1.667 1.667 Methyl 0.083 0.083 0.083 0.083 0.083 0.083 paraben NaOH 8.333 8.333 8.333 8.333 8.333 8.333 External phase Orange 0.167 0.167 0.167 0.167 0.167 0.167 flavour Talc 8.333 8.333 8.333 8.333 8.333 8.333 Total solids 137.263 87.263 127.263 87.263 110.179 85.179

[0058] The characteristics of the suspension produced for both resins are presented in Table 2 below:

TABLE-US-00002 TABLE 2 Characteristics of Formulations 1 to 3 for Indion ™ 204, Purolite ™ C100Ca and without resin Indion ™ 204 Purolite ™ C100Ca Without resin pH Appearance pH Appearance pH Appearance Formulation 5.55 Homogenous 5.63 Homogenous 5.78 Two phase 1 suspension suspension suspension Formulation 5.51 Homogenous/ 5.54 Homogenous/ 5.84 Two phase 2 compact compact suspension suspension suspension Formulation 5.70 Homogenous 5.81 Homogenous 5.98 Two phase 3 suspension suspension suspension

[0059] In Formulation 1 both compositions of resins were homogeneous and they had a smooth feeling on the tongue. It seems that in composition with Purolite™ C100Ca, the taste wasn't desirable enough because it had a more acidic taste due to its strong nature. Despite this fact, it is obvious that both resins can taste mask the extremely bitter taste of drug as the composition without resin didn't have a desirable taste. Also, the formula without resin wasn't indicated as a two phase suspension was noticed after the reconstitution.

[0060] In Formulation 2 both compositions of resins had a desirable aftertaste in contrast to that one without resin where the bitter taste of drug confirmed the efficacy of resins. In this case, the strong acid character of Purolite™ C100Ca didn't affect the taste of the composition due to its lower concentration (40 mg/ml instead of 50 mg/ml). As for their appearance, probably the concentration of suspending agent-Xanthan gum (4.167 mg/ml) was high enough and as a result, the compositions had a poor flow.

[0061] In Formulation 3 both compositions of resins had enhanced palatability compared to that one without resin but it is evident that the resin concentration (25 mg/ml) wasn't adequate to taste mask the API.

[0062] Taking Formulations 1 to 3 into consideration, a composition with a totally accepted palatability isn't yet reached but there are serious indications that DRC 1:0.8 is probably a desirable complex.

[0063] Apart from the palatability screening, a focus on the drug's degradation effect would enhance the research around the most suitable Drug:Resin ratio and appropriate resin. For this reason, the impurities status of DRC 1:1, 1:0.8, 1:0.5 for both resins was recorded with an HPLC method. Impurities data at the zero point are presented in the following tables (Table 3 and 4).

TABLE-US-00003 TABLE 3 Impurities data of DRC 1:1, 1:0.8, 1:0.5 for Indion ™ 204 Specification DRC 1:0.5 DRC 1:0.8 DRC 1:1 Guanine (NMT 0.5%) 0.03 0.03 0.04 Acyclovir (NMT 3.0%) 0.73 0.69 0.68 Formyl VACV (NMT 0.5%) 0.13 0.13 0.13 BVG (NMT 0.5%) ND ND ND Unknown ND ND ND Unknown ND ND ND Unknown ND ND ND Unknown ND ND ND Unknown ND ND ND Total 0.89 0.85 0.85

TABLE-US-00004 TABLE 4 Impurities data of DRC 1:1, 1:0.8, 1:0.5 for Purolite ™ C100Ca Specification DRC 1:0.5 DRC 1:0.8 DRC 1:1 Guanine (NMT 0.5%) 0.07 0.22 0.36 Acyclovir (NMT 3.0%) 0.67 0.71 0.78 Formyl VACV (NMT 0.5%) 0.14 0.16 0.17 BVG (NMT 0.5%) ND ND ND Unknown ND ND ND Unknown ND ND ND Unknown ND ND ND Unknown ND ND ND Unknown ND ND ND Total 0.88 1.09 1.31

[0064] It is evident that Purolite™ C100Ca degrades to a greater extent the drug than the Indion™ 204. More specifically, increasing the Drug:Purolite™ C100 ratio both guanine and acyclovir, the major metabolite of drug, follow an increasing trend. This behavior doesn't appear to Drug:Indion™ 204 complex of any ratio.

[0065] As a result, Indion™ 204 appears as the most suitable resin for the Valaciclovir development and the DRC 1:0.8 and 1:1 are highly recommended due to their lower drug degradation effect. Bearing in mind the palatability screening of Formulations 1, 2 and 3 it is concluded that Drug:Indion™ 204 1:0.8 complex is the most appropriate for the development of Valaciclovir.

[0066] Consequently, in Formulation 4 Drug:Indion™ 204 with ratio 1:0.8 was used. Moreover, xanthan gum was reduced to 50% w/w of initial quantity as its high concentration results in poor flow. A homogeneous suspension of an acceptable taste was prepared. (Table 5)

[0067] Despite this, there is an emergency to reduce the total solids per ml as the preparation of the 100 mg/ml strength, which would follow the weight proportional rule, would encounter a few problems. In Formulation 5 microcrystalline cellulose was erased from the formula as it was slightly detectable on the tongue and even though orange flavor concentration was decreased, the increase in sucralose concentration was sufficient in order to offer desirable taste. (Table 5) Formulation 5 was difficult to be reconstituted; the extremely high quantity of NaOH impedes the powder reconstitution. It is common knowledge that NaOH is a quite strong base and leads to an exothermic reaction posing a threat to development safety.

TABLE-US-00005 TABLE 5 Formulations 4 and 5 mg/ml Ingredients Formulation 4 Formulation 5 Internal Phase Valaciclovir 50.000 50.000 Valaciclovir HCl hydrated 56.180 56.180 Indion ™ 204 40.000 40.000 Xanthan Gum 2.083 2.500 Microcrystalline Cellulose 8.333 — Sucralose 1.667 2.500 Methyl Paraben 0.083 0.083 NaOH 8.333 8.333 External Phase Orange flavour 0.167 0.083 Talc 8.333 1.667 Total solids 125.179 111.346

[0068] Formulations 4 and 5 were prepared with the same manufacturing process as Formulations 1 to 3.

[0069] In order to examine how the ratio Xanthan gum:NaOH influence the pH and appearance of compositions, Formulations 6 and 7 with different ratios were prepared. (Table 6) The manufacturing process followed was the same as in Formulations 1 to 3.

TABLE-US-00006 TABLE 6 Formulations 6 and 7 mg/ml Ingredients Formulation 6 Formulation 7 Internal Phase Valaciclovir 50.000 50.000 Valaciclovir Hydrochloride hydrated 56.180 56.180 Indion ™ 204 40.000 40.000 Xanthan Gum 3.333 2.292 Sucralose 2.500 2.500 Methyl Paraben 0.083 0.083 NaOH 5.000 6.167 External Phase Orange flavour 0.083 0.083 Talc 1.667 1.667 Total solids 108.846 108.972

[0070] Formulation 7 with 6.167 mg/ml NaOH and 2.292 mg/ml xanthan gum was suitable to prepare a homogeneous suspension with a highly acceptable taste. There is no need to adjust the pH of the composition as NaOH forms Van der Waals bonds with the free ions of API hydrochloride (Cl—) that coexist after the Drug:Resin complexation. Indion™ 204 is used to taste mask the bitter taste of drug. However, many references in the literature confirm a wide range of applications as controlled release vehicle as well. This behavior would change dramatically the pharmacokinetics of the development and that's why a dissolution method was immediately applied. The dissolution rate of the drug was recorded using USP II apparatus (paddles) at 50 rpm and 900 ml HCl 0.1N. (Table 7)

TABLE-US-00007 TABLE 7 Dissolution results of DRC 1:0.8 and Formulation 7 Time (min) DRC 1:0.8 Formulation 7 Target 10 95.88% 97.02% >85% 15 97.04% 98.00% 20 97.83% 98.47% 30 98.87% 98.03% 45 99.83% 98.61%

[0071] It is concluded that Indion™ 204 didn't sustain the drug release in the dissolution medium, but on the contrary, the drug content was delivered immediately. Both the complex and the formulation release more than 85% drug at 15 min. Consequently, Formulation 7 fulfilled the expectations for the powder for oral suspension of 50 mg/ml strength. The composition of the 100 mg/ml strength follows the weight proportionality rule.

[0072] Alternative formulations were prepared in order to examine the role of the pH agent and the suspending agent into the product development. Two different excipients were replaced: NaOH (pH agent) and Xanthan gum (suspending agent).

[0073] Firstly, NaOH was replaced by tri-sodium citrate dihydrate. (Table 8) As a conjugate base of a weak acid, citrate can perform as a buffering agent or acidity regulator, resisting changes in pH.

TABLE-US-00008 TABLE 8 Formulations 8 and 9 mg/ml Ingredients Formulation 8 Formulation 9 Internal Phase Valaciclovir 50.000 50.000 Valaciclovir Hydrochloride hydrated 56.180 56.180 Indion ™ 204 40.000 40.000 Xanthan Gum 3.333 2.292 Sucralose 2.500 2.500 Methyl Paraben 0.083 0.083 Tri-sodium citrate dihydrate 22.792 33.208 External Phase Orange flavour 0.083 — Talc 1.667 1.667 Total solids 126.638 135.930

[0074] Formulations 8 and 9 were prepared with the same manufacturing process as Formulations 1 to 3.

[0075] Both formulations led to a homogeneous suspension of good flow. Formulation 8 had a slightly acidic taste that derives probably from the orange flavor and the pH was at a low level. So, Formulation 9 was prepared with increased concentration of pH agent and the orange flavor was erased. The taste was importantly enhanced and the pH was increased. Formulation 8 is similar to the formulation prepared with NaOH (Formulation 6) apart from pH agent concentration. This is predictable due to their nature. NaOH is an extremely strong base in contrast to tri-Sodium citrate that is a weak base.

[0076] The % w/w drug release and the dissolution profile of Formulation 9 in HCL 0.1N is shown in the table below.

TABLE-US-00009 TABLE 9 Dissolution results of DRC 1:0.8 and Formulation 9 Time (min) DRC 1:0.8 Formulation 9 Target 10 95.88%  98.54% >85% 15 97.04%  99.16% 20 97.83%  99.00% 30 98.87%  99.64% 45 99.83% 100.94%

[0077] It is evident from tables 7 and 9 that both pH agents (NaOH and Tri-sodium citrate dihydrate) didn't sustain the drug release as the intermolecular bonds between drug and resin break immediately in HCL 0.1N.

[0078] The taste of Formulation 9 was absolutely acceptable and the homogeneous appearance fulfilled all expectations. The composition of the 100 mg/ml strength follows the weight proportionality rule.

[0079] Xanthan gum was replaced with hydroxypropyl cellulose and hydroxypropylmethyl cellulose. The characteristics of the formulations comprising HPC and HPMC instead of xanthan gum were not estimated as none of suspending agents used prepared a homogeneous suspension. It seems that the cellulose derivatives were not compatible with the other excipients. As a result, it is concluded that xanthan gum appears as a suitable suspending agent having also good stability and viscosity properties over a wide pH and temperature range.

[0080] The preferred compositions of the present invention are illustrated in table 10 below.

TABLE-US-00010 TABLE 10 Preferred compositions of the present invention Ingredients mg/ml Internal Phase Valaciclovir 50.000 50.000 Valaciclovir Hydrochloride hydrated 56.180 56.180 Indion ™ 204 40.000 40.000 Xanthan Gum 2.292 2.292 Sucralose 2.500 2.500 Methyl Paraben 0.083 0.083 NaOH 6.167 — Tri-sodium citrate dihydrate — 33.208 External Phase Orange flavour 0.083 — Talc 1.667 1.667 Total solids 108.972 135.930

[0081] The compositions of 100 mg/ml strength follow the weight proportionality rule.

[0082] The preferred compositions of the present invention are prepared according to the following manufacturing process: [0083] Dry blending of Drug:Indion™ 204 in the ratio 1:0.8; [0084] Kneading the above blend with water in the ratio Drug:Indion™ 204:Water 1:0.8:0.5; [0085] Drying of the wet mass at 40° C.; [0086] Milling of the Drug-Indion™ 204 complex until particle size gets less than 250 μm; [0087] Dry mixing of the Drug-Indion™ 204 complex and the excipients of the internal phase; [0088] Mixing with the excipients of the external phase; [0089] Shifting the powder to eliminate any clumps; [0090] Reconstituting the powder with suitable aqueous diluent.

[0091] Again the impact of drug to resin ratio was tested for formulation 8 (NaOH). The results are shown in table 11 below.

TABLE-US-00011 TABLE 11 mg/ml Form. Form. Form. Form. Form. Form. Ingredients 8 10 11 12 13 14 Internal Phase Valaciclovir 50.000 Valaciclovir 56.180 Hydrochloride hydrated Indion ™ 204 40.000 — 10.000 20.000 50.000 100.000 Xanthan Gum 2.292 Sucralose 2.500 Methyl 0.083 Paraben NaOH 6.167 External Phase Orange 0.083 flavour Talc 1.667 Total solids 108.972 68.972 78.972 88.972 118.072 168.972

[0092] The stability of the formulations was examined at accelerated conditions (40° C.±2° C./RH: 75%±5%) after 6 months & the results of the main known impurities is reported in table 12 below.

TABLE-US-00012 TABLE 12 Form. Form. Form. Form. Form. Form. 8 10 11 12 13 14 DRC DRC DRC DRC DRC DRC Specification 1:0.8 1:0 1:0.2 1:0.4 1:1 1:2 Guanine 0.47 0.63 0.56 0.46 0.48 0.59 (NMT 0.5%) Acyclovir 2.85 4.90 4.40 2.87 2.90 3.50 (NMT 3.0%) Formyl 0.14 0.26 0.27 0.19 0.19 0.23 VACV (NMT 0.5%)

[0093] Considering the stability results, it is evident that formulation trial is stable within a range of API:Resin ratio 1:0.4 up to 1:1. More particularly, the quality characteristics are well within specifications under accelerated storage conditions for 6 m period. Furthermore, it was noticed that API degradation was performed under acidic conditions stressing at low & higher resin content Formulation Trials. As for the palatability of oral suspension, it is also acceptable within the current API:resin ratio range, whereas it was noted that the reconstitution of suspension wasn't feasible at higher ratio.

[0094] Based on the data, it can be stated that cation exchange resin ensures the stability profile of Valacyclovir API in finished product oral suspension as well as the palatability and appearance of oral suspension at the following API:resin ratio range: 1:0.4 till 1:1. Thus, the current range is considered suitable in the context of current invention.

[0095] Several embodiments of the present invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.