Pharmaceutical composition containing levomepromazine and process for the preparation thereof

Abstract

The present invention relates to an improved pharmaceutical composition comprising a therapeutically effective quantity of levomepromazine or a pharmaceutically acceptable salt thereof, as an active ingredient, wherein said composition is an oral solution and a process for the preparation thereof.

Description

[0001] PHARMACEUTICAL COMPOSITION CONTAINING LEVOMEPROMAZINE AND PROCESS FOR THE PREPARATION THEREOF

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to an improved pharmaceutical composition for oral administration, and in particular to a pharmaceutical composition comprising a therapeutically effective quantity of levomepromazine or a pharmaceutically acceptable salt thereof, as an active ingredient, having an improved stability and bioavailability. Furthermore, the present invention relates to a process for the preparation of said pharmaceutical composition.

[0004] BACKGROUND OF THE INVENTION

[0005] Liquid formulations are pharmaceutical dosage forms that are most suitable for patients that have difficulty swallowing solid dosage forms and have been widely used for elderly and pediatric medications to provide easier administration.

[0006] However, little systematic effort has been made to develop liquid formulations for geriatric patients or other adult patients with swallowing difficulties. In absence of any oral liquid formulation available in the market, pharmacies generally follow a practice of preparing solutions or suspensions from available solid formulation by crushing the solid dosage form and adding purified water. If required syrup can also be added to make the suspension palatable.

[0007] Therefore, the commercially available solid dosage form must be compounded into a solution or suspension when needed for children and geriatric patients. Unfortunately, errors during preparation and dosing of such solutions or suspensions prepared from solid formulation have occasionally led to serious overdoses that resulted in various emergencies and required immediate therapeutic intervention. Further, the stability of such solutions / suspensions are very limited and cannot be stored for longer period.

[0008] Levopepromazine is a phenothiazine neuroleptic drug used in psychiatry with pain relieving and antiemetic properties. It possesses anti-emetic, antihistamine and anti-adrenaline activity and exhibits a strong sedative effect. Further, it is used for the relief of severe pain and as a sedative to relieve anxiety and distress associated with severe pain.

[0009] Levomepromazine ’s hydrochloride chemical name is (2R)-3-(2-methoxy-10H-phenothiazin-10- yl)-N,N,2-trimethylpropan-l -amine hydrochloride; and its molecular weight is 364.90.

[0010] Levomepromazine hydrochloride is a white or very slightly yellow crystalline powder, slightly hygroscopic, freely soluble in water and ethanol, practically insoluble in heptane. Levopepromazine hydrochloride falls under Class III of BCS (Biopharmaceutical Classification System) because of its high solubility and low permeability.

[0011] Levomepromazine is commercially available as tablets for oral administration and as solution for injection / infusion under the brand name Nozinan®. Each Nozinan® tablet (hereafter referred to as reference product) contains 25 mg of levomepromazine maleate and the following inactive ingredients: potato starch, calcium hydrogen phosphate, sodium lauryl sulfate, and magnesium stearate. For patients who are unable to swallow whole tablets (such as patients suffering from dysphagia) and who are on medication, it is usually recommended to crush the tablet and suspend it in water, or 5% glucose in water, and immediately administered orally.

[0012] While patient compliance may be increased by this practice, dose strength, drug stability, and pharmacokinetics are compromised, adversely affecting the efficacy of the medication.

[0013] Therefore, there still exists the need to provide a liquid pharmaceutical formulation of levomepromazine, in particular a ready-to-use solution formulation of levomepromazine which exhibits an adequate release of levomepromazine and a process for obtaining a storage-stable and ready-to-use solution which overcomes the related problems of stability and bioavailability of levomepromazine and which is suitable for oral administration without any stability or bioavailability issues. Thus, there is a need for stable and effective liquid formulations for delivering levomepromazine.

[0014] SUMMARY OF THE INVENTION

[0015] It is, therefore, an object of the present invention to provide a storage-stable liquid solution pharmaceutical composition for oral administration comprising levomepromazine or pharmaceutically acceptable salt thereof, as an active ingredient, which overcomes the deficiencies of the prior art.

[0016] It is another object of the present invention to provide a storage-stable, ready-to-use liquid solution for oral administration containing levomepromazine or a pharmaceutically acceptable salt thereof, as an active ingredient, which is stable and bioavailable with sufficient self-life and good pharmacotechnical properties.

[0017] Moreover, it is another object of the present invention to provide a suitable process for the preparation of a storage-stable liquid solution pharmaceutical composition for oral administration containing levomepromazine or pharmaceutically acceptable salt thereof, as an active ingredient, which is effective and reproducible.

[0018] A further aspect of the present invention is to afford a method for the preparation of a storagestable liquid solution for oral administration containing levomepromazine which overcomes the difficulties encountered in pharmaceutical production because of the high solubility of Levomepromazine .

[0019] In accordance with the above objects of the present invention, a storage-stable liquid solution composition for oral administration is provided comprising a therapeutically effective amount of levomepromazine or a pharmaceutically acceptable salt thereof, as an active ingredient, propylene glycol as stabilizing agent and glycerol as co-solvent, wherein said composition has a pH value in the range from 3.5 to 4.5.

[0020] According to another embodiment of the present invention a storage-stable liquid solution composition for oral administration is provided comprising 5.0 mg / mL levomepromazine, propylene glycol in the range from 150 to 300 mg / mL, Glycerol in the range from 200 to 500 mg / mL, saccharin solution, orange flavour, sodium benzoate in the range from 0.2 to 1.0 mg / ml and said composition is having pH value in the range from 3.8 to 4.2.

[0021] According to another embodiment of the present invention, a cost effective and simple process for manufacturing a storage-stable, ready-to-use liquid solution composition for oral administration is provided comprising levomepromazine as an active ingredient, which facilitates drug release and increases the bioavailability of the active ingredient.

[0022] According to another embodiment of the present invention, a process for the preparation of a storage-stable liquid solution composition for oral administration comprising a therapeutically effective amount of levomepromazine or a pharmaceutically acceptable salt thereof, as an active ingredient, is provided, wherein said process comprises the following steps:

[0023] Step 1 : Adding purified water about 40% of the total volume in a main compounding vessel together with the total amount of a stabilizing agent, such as propylene glycol under stirring until complete dissolution and subsequently, adding the total amount of a co-solvent, such as glycerol under continuously mixing until a clear solution is formed;

[0024] Step 2: Adding in the main compounding vessel the total amount of levomepromazine or salt thereof under continuous stirring until the active ingredient is completely dissolved;

[0025] Step 3: Subsequently adding in the main compounding vessel the specified amount of preservative such as Sodium benzoate under stirring until complete dissolution, and then, slowly adding the total amount of a sweetener, such as saccharin sodium and optionally a flavouring agent, such as orange flavor under continuous stirring until a clear solution is formed;

[0026] Step 4: Measuring the pH of the solution in the main compounding vessel and, if required, adjusting said pH to a value from 3.8 to 4.2, by using agents for pH adjustment such as hydrochloric acid or sodium hydroxide solution, and subsequently, adding purified water so as to reach the total water volume as required under stirring until the mixture is homogenous; and

[0027] Step 5: Passing the final levomepromazine solution through a polypropylene cartridge filter of suitable mesh size and then filling the final solution into the designated containers under Nitrogen purging and then, sealing the containers with child resistant, tamper evident screw caps.

[0028] Further preferred embodiments of the present invention are defined in dependent claims 2 to 10 and 13.

[0029] Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] For the purposes of the present invention, a liquid solution pharmaceutical composition comprising levomepromazine or salt thereof is considered to be improved if said composition achieves increased stability and bioavailability by maintaining therapeutically effective drug concentration than the known solid pharmaceutical formulations of levomepromazine.

[0032] For the purposes of the present invention, a liquid solution pharmaceutical composition for oral administration comprising levomepromazine or pharmaceutically acceptable salt thereof, as an active ingredient, is considered to be “stable” if said active ingredient degradates less or more slowly than it does on its own and / or in known pharmaceutical compositions during storage. An excipient is considered to be “incompatible” with said active ingredient or salt thereof if it promotes the degradation of said active ingredient, that is to say, if said active ingredient precipitates / degradates more or faster in the presence of said excipient when compared with the precipitation / degradation of said active ingredient on its own. The terms “incompatibility”, “compatible” and “compatibility” are defined accordingly.

[0033] The aim of the present invention was the development of liquid solution formulations containing levomepromazine in order to achieve strong therapeutic effects and to ensure patient compliance and convenience in the management of psychotic conditions and in the relief of severe chronic pain. Under this scope, several different solutions were prepared and studied for their stability or incompatibility. In these studies, the formation of a solid degradation impurities was investigated during product storage, in order to assess the influence of conventionally used excipients like cosolvents, stabilizing agents, buffers, preservatives, sweeteners and flavouring agents.

[0034] It has been surprisingly found that the object of the present invention is achieved by adjusting the concentration of the active ingredient and the pH value of the mixture in the final solution, and by using a stabilizing agent such propylene glycol and co-solvent such as glycerol in specified concentrations in order to prevent the formation of solids precipitate / degradation impurities and to improve the physicochemical stability of the active ingredient. Overcoming this technological hurdle enabled the preparation of a storage-stable ready-to-use liquid solution composition containing effective amount of levomepromazine.

[0035] Accordingly, in a first aspect the present invention provides a storage-stable liquid composition for oral administration comprising from about 0.05 to about 0.6% w / v levomepromazine hydrochloride expressed as weight / volume units (g / 100 mL). In the liquid composition of the present invention, levomepromazine and salts thereof can be used at different solvates or degrees of hydration, and crystalline forms.

[0036] In a preferred embodiment, the composition comprises about 0.5% w / v levomepromazine. In addition to levomepromazine the composition of the invention may comprise excipients suitable for oral liquid solution formulations and preferably co-solvents, stabilizing agents, surfactants, pH buffers or adjusting agents, preservatives, sweeteners and flavouring agents. In a preferred embodiment the composition contains, independently from one another: propylene glycol as stabilizing agent; glycerol as co-solvent; sodium benzoate as preservative; saccharin sodium as sweetener; orange flavour as flavouring agent; sodium hydroxide or hydrochloric acid as pH adjusting agents.

[0037] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, stabilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

[0038] Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0039] To achieve stability of the product, the pH value of the composition is adjusted in the range from 3.5 to 4.5, preferably from 3.8 to 4.2. It was found that outside this pH range, a precipitate / impurities may form during product storage regardless of the addition of stabilizing agents.

[0040] In the first basic studies on the present invention it was found that in the process of formulating a liquid solution containing levopemrpomazine unexpected stability problems arise when the pH of the composition was above 6.0. Best results in terms of absence of precipitate were observed in pH range between 3.5 to 4.5, with particularly good results in the pH range from 3.8 to 4.2.

[0041] The liquid composition of the present invention is used to prepare ready-to-use oral solution. To this purpose, containers appropriate for oral use are filled with the liquid solution optionally sealing the containers with child resistant, tamper evident screw caps.

[0042] The aqueous vehicle of the pharmaceutical compositions provided herein can be a buffering system. The buffering system may be selected from a phosphate, citrate, tartrate or acetate buffer.

[0043] The pharmaceutical compositions provided herein can further comprise additional excipients. For example, the use of additional wetting agents or surfactants in a pharmaceutical composition may increase the physical stability.

[0044] The pharmaceutical carrier may also contain preservatives as are known in the art.

[0045] The pharmaceutical compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of liquid dosage form for oral administration.

[0046] Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and provide a product exhibiting excellent bioavailability and palatability.

[0047] The composition of the present invention may include further additives (alone or in a combination) such as acids, adjuvants, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, moisturizers, buffering agents, pH control agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, surfactants, coloring agents, preservatives, wettig agents etc..

[0048] Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame, sucralose and the like.

[0049] Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, orange flavour, spearmint flavour, peppermint flavour and the like.

[0050] One of the main objects of the present invention was to prepare a product with acceptable stability. For this reason, the composition of the present invention was exposed to normal and accelerated stability studies according to the current ICH guidelines.

[0051] The results showed that the stability of the present invention was good (i.e. total impurities were not increased throughout normal and accelerated conditions). The selection of appropriate materials (excipients etc.) should be done carefully in order to avoid any incompatibility problems or non-compliance with EMA and FDA guidelines for inactive ingredients.

[0052] The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:

[0053] EXAMPLES

[0054] Compatibility studies of Levomepromazine hydrochloride

[0055] Prior to evaluating the potential effects of inactive ingredients on the stability of Levomepromazine hydrochloride oral solution, an extensive compatibility study was carried out for the identification of potential drug - excipient interactions. The compatibility protocol was designed to include the pH range from 3.0 to 6.0.

[0056] Drug-excipient interactions were monitored against related substances through stability indicating HPLC method.

[0057] Example 1 - Compositions 1 - 6 containing 0.5% Levomepromazine hydrochloride for establishing the pH-stability profile of Levomepromazine hydrochloride oral solution

[0058] The pH stability profile of Levomepromazine hydrochloride in oral solution was evaluated in the pH region 3.0 -6.0. For the purpose of pH stability profile evaluation of Levomepromazine hydrochloride oral solution, liquid vehicles of the same composition containing Levomepromazine hydrochloride at the concentration of 5 mg / mL were prepared and pH -adjusted in the above specified pH range before being placed at stressed heat conditions for one month at 40°C and 55°C. The impurity profiles of the prepared solutions (compositions 1 - 6 as presented in Table 1) were monitored at time period T=0 days and T=30 days and were placed at stressed heat storage conditions, providing essential information of any pH -related instability of Levomepromazine.

[0059] TABLE 1 : Composition 1 - 6 of the present invention.

[0060] Unless otherwise indicated, all steps in this procedure were carried out at room temperature. The preparation of compositions 1 to 6 of Example 1 of the present invention was prepared according to the following process: Approximately 85% of the total volume of purified water was added in the compounding vessel and the total amount of levomepromazine hydrochloride was added under stirring until the active ingredient is completely dissolved and purified water was added to the fill volume as required. The final pH value of the solution was measured with a calibrated pH-meter and, if necessary, it was adjusted to pH value according to Table 1 by using hydrochloric acid solution. The stability results of compositions 1 - 6 of Example 1 are presented below (see Table 2, 3 and 4).

[0061] TABLE 2: Stability results of Levomepromazine hydrochloride oral solution Compositions 1 - 6 of Example 1 at time period T = 0 days

[0062] *B.R.L.: Below Reporting Limit (0.1%), B.Q.L: Below Quantitation Limit, N.D.: Not Detected Upon monitoring of Levomepromazine hydrochloride solution compositions 1 - 6 of Example 1 , the chemical quality of levomepromazine was affected by the pH profile. The levels of degradation impurities arisen upon exposure to severe heat stresses demonstrated the interaction of the pH factor with the reactivity of the moiety. Accordingly, the pH range appeared to have an impact on the physical stability.

[0063] Though the pH variable was associated with chemical instability, its potential to interact with the dissolution process of levomepromazine strengthened the necessity for optimizing the pH value of the solution. The pH range from 3.5 to 6.0 was selected for further monitoring. This choice was substantiated by the fact that it represents a favourable substrate for the majority of the preservatives to exhibit their antimicrobial properties. TABLE 3: Stability results of Levomepromazine hydrocloride solution Compositions 1- 6 of Example 1, at long-term conditions time period T= 30 days, (Temperature 55±2°C, 20±5% relative humidity) *B.R.L.: Below Reporting Limit (0.1%), B.Q.L: Below Quantitation Limit, N.D.: Not Detected

[0064] TABLE 4: Stability results of Levomepromazine hydrocloride solution Compositions 1- 6 of Example 1, at long-term conditions time period T= 30 days, (Temperature 40±2°C, 75±5% relative humidity) *B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected

[0065] The pH - stability profile of the aqueous solutions of Levomepromazine HC1, signified the pH - dependent stability behaviour of the molecule. According to the obtained data, a narrow pH range was indicated for optimal quality performance. In particular, minimization of the chemical reactivity was observed at solutions with pH value adjusted within the range 4.0 - 5.0 (see compositions 3 and 4), characterised by low levels of the oxidatively-induced impurity B.

[0066] Departure from this range was accompanied by deterioration of the impurity profile. Lowering the pH value to 3 (composition 1) increased the formation rates of Impurity B, promoting the oxidation of Levomepromazine HC1. A less intense decomposition was recorded for the pH value of 6 but still suboptimal when compared to the pH range 4.0 - 5.0. It is of interest that compositions buffered in the pH range 5-6 suffered physical change in the form of precipitation. The above described behaviours were captured for both conditions, 40°C and 55 °C, with the latter resulting in more exaggerated breakdown. Acknowledging the stability-modulating role of the pH variable, it was found reasonable to maintain pH within narrow limits and more specifically in the range 3.5 - 4.5 for the remainder of the studies.

[0067] Upon standardizing the optimal pH region, a series of compatibility studies were executed, challenging the stability performance of levomepromazine hydrocloride with various excipients. The following excipients were the most preferred excipients used in oral solutions according to the present invention and were subjected to evaluation: co-solvents such as propylene glycol, glycerol, and mixtures thereof, buffering agents such as sodium citrate dihydrate, citric acid, and mixtures thereof, preservatives such as sodium benzoate and sweeteners such as saccharin solution. Aqueous solutions of levomepromazine hydrochloride with said excipients were incubated at accelerated ICH conditions and elevated temperature for a time period of one month. In the context of the same study, levomepromazine oral solution buffered outside the upper value of the pH range was also evaluated. Furthermore, the effect of the co-solvents, preservatives, buffering system was also monitored.

[0068] Example 2 - Compositions 7 - 12 containing 0.5% Levomepromazine hydrocloride with various excipients were manufactured to investigate their impact on the formation of the precipitate

[0069] Compositions 7 - 12 of Example 2 of the present invention (see Table 5) were prepared according to the following manufacturing process: Purified Water was added in a main compounding vessel and the total amount of stabilizing agent propylene glycol was added under stirring until complete dissolution. Subsequently, the total amount of co-solvents, such as Glycerol, Liquid Sorbitol or Liquid Maltitol was added under continuously mixing until a clear solution is formed. Subsequently, the total amount of the active ingredient levomepromazine hydrochloride was added in the main compounding vessel under continuous stirring until the active ingredient is completely dissolved. The final pH of the solution in the main compounding vessel was measured and, if required, it was adjusted to specified pH value by using 10% solutions of HCL solution or Sodium hydroxide solution. Subsequently, purified water was added to the fill volume as required under stirring until the mixture is homogenous. The final levomepromazine hydrochloride solution was passed through a a polypropylene cartridge filter of suitable mesh size and then filling the final solution into the designated containers with or without Nitrogen purging. The generated results of said compositions are provided in the tables below (see Table 6, 7 and 8) TABLE 5: Compositions 7 - 12 of the present invention.

[0070] TABLE 6: Stability results of Levomepromazine hydrochloride oral solution Compositions 7 - 12 of Example 2 at time period T = 0 days

[0071] *B.R.L.: Below Reporting Limit (0.1%), B.Q.L: Below Quantitation Limit, N.D.: Not Detected TABLE 7: Stability results of Levomepromazine hydrocloride solution Compositions 7- 12 of Example 2, at long-term conditions time period T= 30 days, (Temperature 55±2°C, 20±5% relative humidity) *B.R.L.: Below Reporting Limit (0.1%), B.Q.L: Below Quantitation Limit, N.D.: Not Detected

[0072] TABLE 8: Stability results of Levomepromazine hydrocloride solution Compositions 7- 12 of Example 2, at long-term conditions time period T= 30 days, (Temperature 40±2°C, 75±5% relative humidity) *B.R.L.: Below Reporting Limit (0.1%), B.Q.L: Below Quantitation Limit, N.D.: Not Detected

[0073] Significant inhibitory effects on the degradation kinetics of Levomepromazine were exerted by the inclusion of certain organic solvents. The highest positive impact on the stability of Levomepromazine HC1 was seen in the presence of propylene glycol (compositions 7,8 and 9) that yielded the lowest amount of Impurity B throughout the compatibility studies. It can be postulated that propylene glycol acts as oxygen scavenger protecting the active ingredient from oxidation. This satisfactory performance remained unaffected within the pH range 4.0-5.0. Stabilization but of lesser magnitude was imparted by the addition of glycerol (composition 12) while no appreciable oxidative suppression was detected in compositions containing sorbitol or maltitol (compositions 10 and 11).

[0074] Example 3 - Compositions 13 - 16 containing 0.5% Levomepromazine 12ydrochloride with various excipients were manufactured to investigate their impact on the formation of the precipitate

[0075] TABLE 9: Compositions 13- 16 of the present invention.

[0076] Compositions 13 - 16 of Example 3 of the present invention (Table 9) were prepared according to a similar manufacturing process as described in Example 2 of the present invention, wherein instead the co-solvents, the buffering system or the sweeteners were added. The generated results of said compositions are provided in the tables below (see Table 10, 11 and 12). TABLE 10: Stability results of Levomepromazine hydrochloride oral solution Compositions 13 - 16 of Example 3 at time period T = 0 days *B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected

[0077] TABLE 11: Stability results of Levomepromazine hydrocloride solution Compositions 13- 16 of Example 3, at long-term conditions time period T= 30 days, (Temperature 55±2°C, 20±5% relative humidity) *B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected TABLE 12: Stability results of Levomepromazine hydrocloride solution Compositions 13- 16 of Example 3, at long-term conditions time period T= 30 days, (Temperature 40±2°C, 75±5% relative humidity)

[0078] *B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected

[0079] The inclusion of citrate (Composition 15) or phosphate (Composition 16) buffering systems affected adversely the chemical profile of the active compound at elevated temperature, promoting higher formation rates of Impurity B than those yielded from trials pH-adjusted with HC1. The transition metals present in trace amounts in buffers possibly participate catalytically in the oxidation of Levomepromazine, providing rationale for their exclusion from the formulation development task.

[0080] Of the tested sweeteners, sodium saccharin (Composition 13) gave a similar impurity profile to that assigned to the pure aqueous trial of Levomepromazine with pH value at 4.0, inferring its negligible interaction potential and thus demonstrating compatibility. On a comparative basis, sucralose accelerated the oxidation of the active compound at 55 °C, showing sub-optimal performance.

[0081] Example 4 - Evaluation / selection of preservatives, antioxidants and chelating agents- Compositions 17 - 22 containing 0,5% Levomepromazine hydrocloride

[0082] Compositions 17 - 22 of Example 4 of the present invention (Table 13) were prepared according to a similar manufacturing process as described in Example 2 of the present invention, wherein instead the co-solvents, preservatives or antioxidants / chelating agents were added. The generated results of said compositions are provided in the tables below (see Table 14, 15 and 16). TABLE 13: Compositions 17 - 22 of the present invention.

[0083] TABLE 14: Stability results of Levomepromazine hydrochloride oral solution Compositions 17 - 22 of Example 4 at time period T = 0 days TABLE 15: Stability results of Levomepromazine hydrochloride solution Compositions 17- 22 of Example 4, at long-term conditions time period T= 30 days, (Temperature 55±2°C, 20±5% relative humidity) B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected

[0084] TABLE 16: Stability results of Levomepromazine hydrocloride solution Compositions 17- 22 of Example 4, at long-term conditions time period T= 30 days, (Temperature 40±2°C, 75±5% relative humidity) The incorporation of antioxidants and chelating agents [i.e. ascorbic acid (Composition 20), sodium metabisulfite (Composition 21)] as well as the combination of sodium metabisulfite with the chelating agent disodium edetate (composition 22) failed to prevent the oxidation of Levomepromazine to the corresponding sulfoxide derivative. Compared to antioxidant - free formulae, ascorbic acid oxidized massively the active ingredient at elevated temperature accompanied by extensive discolouration. Milder but significant decomposition occurred at 40 °C / 75% RH. Similar degradation patterns of varying intensity were assigned to sodium metabisulfite whose destructive effect was potentiated by the addition of disodium edetate. Though these excipients were incorporated to inhibit the repeatedly documented oxidative degradation pathway, it was surprisingly seen that these excipients favoured the formation of degradation products. It seems that the antioxidants under evaluation reacted in the solution (e.g. possibly with oxygen) producing reactive species capable of oxidizing Levomepromazine HC1. This hypothesis can perfectly describe the negative impact of ascorbic acid on the oxidation rates of the active compound. Ascorbic acid degrades greatly in aqueous solutions at pH 4.0 and higher, forming several by - products with oxidizing potential. With the ascorbic acid - containing compatibility trial posing unfavourable conditions for its integrity, the recovered impurity profile is exemplified. The instability caused by the other antioxidant / chelating agents might be attributed to higher oxidation potential of the API compared to them or to inappropriate concentrations used for the needs of the exercise.

[0085] No appreciably different degradation profiles were obtained for the three preservatives under evaluation. For all of them, a higher interaction potential was noted at the stressed condition of 55°C.

[0086] Further, the effectiveness of nitrogen purging in the headspace of the containers was unequivocally evidenced in all compositions processed with this treatment (compositions 2, 6, 7 and 8). It is remarkable that the removal of the reactive oxygen from the surrounding space of the solution retarded markedly the oxidative degradation of the active ingredient even in compositions containing components with destabilising impact. In view of this protective activity, this processing treatment was incorporated in the manufacturing process.

[0087] Example 5 -Compositions 23 - 24 containing 0.5% Levomepromazine hydrochloride according to the present invention

[0088] Though the delivery of a vehicle that contains the maximum proposed levels for each excipient seemed the obvious solution to the problem, constraining factors related to the safety profile of propylene glycol deprived the formulator from such an approach. To determine the maximum level of propylene glycol that is devoid of concerns, the latest safety recommendations of the EMA surrounding this excipient were advised. Considering the maximum dose of treatment that can be administered in a female patient of 58 kg, the maximum quantity of propylene glycol cannot exceed the amount of 241 mg / ml. For these calculations, the maximum dose assigned to the solid forms (i.e. tablets) 600 mg was considered, even though half of said dose (300 mg) is recommended for the oral solution. This approach was adopted to ensure the largest safety margin in the unlikely event that the posology of solid form is prescribed.

[0089] To balance the output of the experimental design with the safety precautions, the following compositions were produced and assessed for their stability. The maximum level of glycerol was set to 400 mg / ml. Higher amounts of this component resulted in increased compounding times, complicating the manufacturability of the product.

[0090] The below formulae were stored at long term and accelerated conditions. TABLE 17: Compositions 23 - 24 of the present invention.

[0091] Compositions 23 - 24 of Example 5 of the present invention (see Table 17) were prepared according to the following manufacturing process: Purified Water was added in a main compounding vessel and the total amount of stabilizing agent propylene glycol was added under stirring until complete dissolution. Subsequently, the total amount of co-solvent Glycerol was added under continuously mixing until a clear solution is formed. Subsequently, the total amount of the active ingredient levomepromazine hydrochloride was added in the main compounding vessel under continuous stirring until the active ingredient is completely dissolved. Then, the specified amount of preservative Sodium benzoate was added in the main compounding vessel under stirring until complete dissolution, and then, the total amount of saccharin sodium as a sweetener, and orange flavor as flavouring agent were added slowly under continuous stirring until a clear solution is formed. Then, the final pH of the solution in the main compounding vessel was measured and, if required, it was adjusted to a pH value between 3.8 - 4.2 by using 10% solutions of HCL solution or Sodium hydroxide solution. Subsequently, purified water was added to the fill volume as required under stirring until the mixture is homogenous. The final levomepromazine hydrochloride solution was passed through a polypropylene cartridge filter of suitable mesh size and then filling the final solution into the designated containers under Nitrogen purging. The generated results of said compositions are provided in the tables below (see Table 18, 19 and 20).

[0092] As shown in Table 17, sodium benzoate and sodium saccharin were included to serve preservation and palatability functionalities. TABLE 18: Stability results of Levomepromazine hydrochloride oral solution Compositions 23 - 24 of Example 5 of the present invention at time period T = 0 days

[0093] B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected

[0094] TABLE 19: Stability results of Levomepromazine hydrocloride solution Compositions 23- 24 of Example 5, at long-term conditions time period T= 90 days, (Temperature 40±2°C, 75±5% relative humidity)

[0095] B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected TABLE 20: Stability results of Levomepromazine hydrocloride solution Compositions 23- 24 of Example 5, at long-term conditions time period T= 90 days, (Temperature 25±2°C, 60±5% relative humidity)

[0096] B.R.L.: Below Reporting Limit (0.1%), N.D.: Not Detected

[0097] For the interpretation of the above stability data, the formation rates of “Impurity B” were considered to determine the quality performance and viability of the proposed compositions. When viewing the accelerated stability data of the reference and the compositions 23 and 24 according to the present invention, the advanced stability behaviour of the latter was clearly demonstrated. Despite the severity of the treatment, both proposed formulations retained potency and purity within specifications, whereas the branded product suffered increased decomposition. The same conclusion was reached when comparing the impurity profiles recovered at long -term conditions. Focusing on the proposed compositions, a comparatively higher stabilizing effect characterized the formula containing the highest content of organic solvents. This effect was mostly apparent at the accelerated temperature and diminished at normal storage whereby equivalent and acceptable profiles were obtained. Provided that the degree of oxidative suppression of composition 24 was not exceptionally larger than that observed for composition 23, the latter one was selected as the optimal one affording both quality and safety.

[0098] Overall, the optimum levels of the concerned formulation variables for the delivery of a viable composition according to the present invention were found to be as follows:

[0099] Propylene glycol as stabilizing agent in a concentration from 200 to 300mg / ml, preferably 150 mg / ml

[0100] Glycerol as a cosolvent in a concentration from 249 to 500 mg / ml, preferably 400 mg / ml.

[0101] The vehicle was then fine-tuned against preservation and organoleptic aspects as discussed in the following sections. All compatibility studies demonstrated thermal stability from a chemical perspective, as manifested by the extremely low level of degradants. Conversely, physical destabilization in the form of precipitation occurred in certain pH values.

[0102] In view of the above outcome and taking into consideration the pH limitations on the effectiveness and stability of the safest preservatives for pharmaceutical use, such as sodium benzoate and paraben-based derivatives that dictate environments with pH not greater than 6.0 and more preferably not greater than 6.0, the optimum pH range for levomepromazine solution is from 3.5 to 4.5.

[0103] The pharmaceutical compositions according to the present invention are characterized by excellent pharmacotechnical properties. Thanks to these properties, the liquid dosage forms prepared by the process according to the present invention exhibit excellent technical characteristics including dissolution rate, stability, palatability and bioavailability.

[0104] While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

CLAIMS1. A storage-stable liquid solution pharmaceutical composition for oral administration comprising a therapeutically effective amount of levomepromazine or a pharmaceutically acceptable salt thereof, as an active ingredient, a stabilizing agent such as propylene glycol and a co-solvent such as glycerol, wherein said composition has a pH value in the range from 3.5 to 4.5.

2. The liquid composition according to claim 1, wherein Levomepromazine is in the form of hydrochloride salt.

3. The liquid pharmaceutical composition according to claim 1 , wherein said pH range is preferably from 3.8 to 4.2.

4. The liquid pharmaceutical composition according to claim 1, wherein said Levomepromazine concentration is in the range from 0.5 mg / ml to 6 mg / ml.

5. The liquid pharmaceutical composition according to claim 2, wherein said composition further comprises at least one of the pharmaceutically acceptable excipients selected from co-solvents, sweeteners, buffering agents, preservatives, pH adjusting agents, flavouring agents, antioxidants, chelating agents, wetting agents, suspending agents, or mixtures thereof.

6. The liquid pharmaceutical composition according to claim 2, wherein said composition comprises propylene glycol in the range from 200 to 300 mg / ml and glycerol in the range from 240 to 500 mg / ml.

7. The liquid pharmaceutical composition according to claim 5, wherein said propylene glycol concentration is preferably 150 mg / ml and said glycerol concentration is 400 mg / ml.

8. The liquid pharmaceutical composition according to any preceding claim, wherein said composition further comprises sodium saccharin as sweetener9. The liquid pharmaceutical composition according to any preceding claim, wherein said composition further comprises orange flavour as a flavouring agent.

10. The liquid pharmaceutical composition according to any preceding claim, wherein said composition further comprises sodium benzoate as preservative.

11. A storage-stable liquid solution composition for oral administration comprising 5.0 mg / mL levomepromazine, propylene glycol in the range from 150 to 300 mg / mL, Glycerol in the range from 200 to 500 mg / mL, saccharin solution, orange flavour, sodium benzoate in the range from 0.2 to 1.0 mg / ml and said composition is having pH value in the range from 3.5 to 4.5, preferably from 3.8 to 4.0.

12. A process for the preparation of a storage-stable liquid solution composition for oral administration comprising a therapeutically effective amount of levomepromazine or a pharmaceutically acceptable salt thereof, as an active ingredient, wherein said process comprises the following steps:Step 1: Adding purified water about 40% of the total volume in a main compounding vessel together with the total amount of a stabilizing agent, such as propylene glycol under stirring until complete dissolution and subsequently, adding the total amount of a co-solvent, such as glycerol under continuously mixing until a clear solution is formed;Step 2: Adding in the main compounding vessel the total amount of levomepromazine or salt thereof under continuous stirring until the active ingredient is completely dissolved;Step 3: Subsequently adding in the main compounding vessel the specified amount of preservative such as Sodium benzoate under stirring until complete dissolution, and then, slowly adding the total amount of a sweetener, such as saccharin sodium and optionally a flavouring agent, such as orange flavor under continuous stirring until a clear solution is formed;Step 4: Measuring the pH of the solution in the main compounding vessel and, if required, adjusting said pH to a value from 3.8 to 4.2, by using agents for pH adjustment such as hydrochloric acid or sodium hydroxide solution, and subsequently, adding purified water so as to reach the total water volume as required under stirring until the mixture is homogenous.

13. The process for the preparation a storage-stable liquid solution composition according to claim 12, wherein further comprises a step of filtering the final levomepromazine solution obtained in step 4 through a polypropylene cartridge filter of suitable mesh size and then filling the final solution into the designated containers under Nitrogen purging and then, sealing the containers with child resistant, tamper evident screw caps.

Images