Phenobarbital oral composition and method of manufacture / use thereof

Abstract

A phenobarbital composition is provided that is suitable for oral administration in a human subject. The composition comprises a pharmaceutically effective amount of phenobarbital or a salt thereof; and at least one solvent selected from the group comprising or consisting of short, medium and / or long chain triglycerides.

Description

[0001] Phenobarbital Oral Composition and Method of Manufacture / Use Thereof

[0002] This invention relates to a phenobarbital oral composition, and particularly to a phenobarbital solution suitable for oral administration to a human subject, and method of manufacture and / or use thereof.

[0003] Phenobarbital is a member of the class of barbiturates and is commonly used as an anticonvulsant to treat certain types of epilepsy and seizures. It can also be used to treat insomnia and anxiety. It may be administrated intravenously or taken orally. The chemical structure of Phenobarbital is set out below.

[0004] Phenobarbital’s mechanism of action increases the duration of time chloride channels are open, depressing the central nervous system. This action occurs by acting on GABA-A receptor subunits. When phenobarbital binds to these receptors, the chloride ion gates open and stay open, allowing a steady flow of these ions into neuronal cells. [1] This action hyperpolarizes the cell membrane, increasing the action potential threshold. This increase in action potential is why this drug is effective in treating seizures. It is rapidly and completely absorbed after oral or IV administration. [1] The time of peak plasma concentration ranges from 30 minutes to 1 hour for oral formulations and is around 5 minutes for IV injection.

[0005] It is currently known to provide phenobarbital in tablet form or as a liquid for intravenous injection. There are liquid formulations available for taking orally but they contain high levels of alcohol (i.e. 40% ethanol), which is not suitable for certain patient groups as it can lead to addictive central nervous system (CNS) depressive effects. In fact both UK and US patient information for prior art phenobarbital formulations advise against consuming alcohol while taking barbiturates. In addition, phenobarbital aqueous solutions have poor physical and chemical stability. For example, oral phenobarbital solutions that use only water as the vehicle typically have a shelf life of only about 8 months.

[0006] For patients who have difficulty swallowing, such as elderly patients, stroke patients, children and / or the like, there is a need for a safe and cost effective liquid oral dosage form of phenobarbital. There is also a need to provide a stable oral liquid formulation that has the same or similar bioequivalence of the approved tablet form of phenobarbital. This helps to reduce the risk to patients if they switch between a tablet form and a liquid form of phenobarbital.

[0007] It is therefore an aim of the present invention to provide a stable phenobarbital composition suitable for oral administration in a human subject which overcomes the abovementioned problems.

[0008] It is a further aim of the present invention to provide a method of manufacturing a stable phenobarbital composition suitable for oral administration in a human subject which overcomes the abovementioned problems.

[0009] It is a yet further aim of the present invention to provide a method of use of a stable phenobarbital composition for oral administration in a human subject.

[0010] According to a first aspect of the present invention there is provided a phenobarbital composition suitable for oral administration in a human subject, said composition comprising a pharmaceutically effective amount of phenobarbital or a salt thereof; and at least one solvent selected from the group comprising or consisting of short, medium or long chain triglycerides.

[0011] Preferably the composition is in the form of a solution suitable for oral administration or is an oral solution. Preferably the at least one solvent comprises or consists of medium chain triglycerides.

[0012] Preferably a short chain triglyceride has between 1-6 carbon atoms.

[0013] Preferably a medium chain triglyceride has between 7-12 carbon atoms, and further preferably is considered to contain predominandy 8 & 10 Carbon atoms.

[0014] Preferably a long chain triglyceride has greater than 12 carbon atoms and yet further preferably has between 18-24 carbon atoms.

[0015] Preferably the triglycerides or medium chain triglycerides include any or any combination of Miglyol®, Miglyol® 812 N (preferably a mixture of C6, C8, CIO, and C12 triglycerides), CAS73398-61-5, Caprylic / Capric Triglyceride, fractionated medium chain coconut fatty acids, Miglyol® 81 ON, coconut oil, palm kernel oil, corn oil, soyabean oil, cod liver oil, safflower oil, almond oil, soybean oil, peanut oil, plant derived oil, rapeseed oil, flaxseed oil, cottonseed oil, sesame oil, sunflower oil, walnut oil, ground nut oil, olive oil and / or the like.

[0016] Preferably the at least one solvent or medium chain triglycerides is used in an amount equal to or greater than approximately 75% w / v of the solution, equal to or greater than approximately 80% w / v of the composition, equal to or greater than approximately 85% w / v of the composition, equal to or greater than approximately 90% w / v of the composition, equal to or greater than approximately 95% w / v of the composition.

[0017] In a preferred embodiment the at least one solvent or medium chain triglycerides is used in an amount between approximately 80% w / v - 99% w / v of the composition, further preferably approximately 96% w / v — 99% w / v of the composition, and yet further preferably approximately 96.5%w / v of the composition.

[0018] In one embodiment the phenobarbital used in the composition is phenobarbital base and / or phenobarbital sodium. In one example the phenobarbital base is preferred due to its increased solubility in the at least one solvent or medium chain triglycerides. Preferably the phenobarbital base or salt thereof is used in an amount of approximately 1% w / v or less of the composition; and further preferably is used in an amount of approximately 0.5% w / v or less.

[0019] Preferably the phenobarbital or salt thereof used in the composition is 50mg / 5ml or 25mg / 5ml.

[0020] In one embodiment the composition contains no co-solvent (i.e. no additional solvent or solubiliser to the triglycerides) . For example, in a 25mg / 5ml phenobarbital oral composition, the Applicants have found that no co-solvent is necessary.

[0021] In one example, the composition comprises or consists of 0.5% w / v of phenobarbital, 99-99.5% w / v of a short, medium and / or long chain triglyceride, and optionally 0.5% w / v flavouring agent. Yet further preferably the triglyceride is a medium chain triglyceride, such as for example Miglyol®.

[0022] In one embodiment the composition includes at least one co-solvent or solubiliser to help solubilise the phenobarbital or salt thereof in solution. For example, in a 50mg / 5ml phenobarbital oral composition or solution is may be preferable to include at least one co-solvent or solubiliser.

[0023] Preferably the at least one co-solvent or solubiliser includes or consists of Diethylene Glycol Monoethyl Ether, Transcutol® or a Transcutol® High Purity (HP) grade (or CASH 1-90-0). This solubiliser or co-solvent typically helps to allow an ethanol free composition or solution to be provided, which is advantageous for use with certain patient groups.

[0024] Preferably the at least one solubiliser or co-solventincludes any or any combination of Diethylene Glycol Monoethyl Ether, Transcutol® HP, Transcutol®(CASlll-90- 0), Ethanol, Propylene Glycol, Caproyl® 90, Propylene Glycol Mono caprylate, CAS 31565-12-5 (contains propylene glycol esters of caprylic acid), one or more sugar alcohols, glycerol, sorbitol, mannitol and / or the like.

[0025] Preferably the at least one solubiliser or co-solvent is used in an amount of approximately 1% w / v - 20% w / v of the composition. Preferably the at least one co-solvent or solubiliser is used in an amount of approximately 5% w / v or less.

[0026] Preferably the at least one co-solvent or solubiliser is used in an amount of approximately 2% w / v of the composition + / -0.5% w / v of the composition.

[0027] In one example the at least one co-solvent or solubiliser is Transcutol® or Transcutol® HP (Diethylene Glycol Monoethyl Ether or CASH 1-90-0) and is used in an amount of approximately 2% w / v of the composition.

[0028] In one example the at least one co-solvent or solubiliser is ethanol and is used in an amount of approximately 20% w / v of the composition.

[0029] Preferably the composition includes or consists of approximately 1% w / v of phenobarbital base or a salt thereof, approximately 97% w / v short, medium and / or long chain triglycerides and approximately 2% w / v of Transcutol® HP (Diethylene Glycol Monoethyl Ether), and optionally at least one flavouring agent. Yet further preferably the composition comprises 97% w / v of medium chain triglycerides.

[0030] Preferably the % w / v amount of medium chain triglycerides is reduced by the % w / v of the at least one flavouring agent that may be used in the composition.

[0031] Preferably the composition includes at least one flavouring agent.

[0032] Preferably the at least one flavouring agent include any or any combination of a medium chain triglyceride based flavouring agent, a propylene glycol based flavouring agent, an ethanol based flavouring agent, an isopropyl alcohol based flavouring agent, raspberry, lime, lime, peppermint, orange, orange, raspberry, natural flavouring agents of the any forementioned agents and / or the like.

[0033] Preferably the at least one flavouring agent are used in an amount of 0.1% w / v -1.5 % w / v of the composition, further preferably 0.2-0.5% w / v of the composition.

[0034] In one embodiment the composition is preservative-free (i.e. contains no preservative agents).

[0035] In one embodiment the composition includes one or more preservative agents. Preferably the one or more preservative agents includes any or any combination of ethanol, one or more anti-oxidant agents, one or more hydroxybenzoates and / or the Eke.

[0036] Preferably the one or mote preservative agents contained in the composition are used in an amount of approximately 1-20% w / v of the solution.

[0037] Preferably the composition includes one or mote sweetening agents.

[0038] Preferably the one or more sweetening agents include any or any combination of Saccharin base, Advantame® (N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-oc- aspartyl]-L-phenylalanine 1-methyl ester monohydrate), (CAS 714229-20-6),— (an N- substituted derivative of aspartame), Neotame (L-phenylalanine, N-[N-(3,3-dimethylbutyl) L-a-aspartyl]-, 1-methyl ester), (CAS 165450-17-9) ,( an aspartame analog) and / or the like. Preferably the one or more sweetening agents contained in the composition are used in an amount of approximately 0.01-2% w / v of the composition.

[0039] In one embodiment the phenobarbital oral composition comprises or consists of a pharmaceutically effective amount of phenobarbital or a pharmaceutically acceptable salt thereof; at least one solvent selected from the group consisting of short, medium and / or long chain triglycerides; and optionally one or more flavouring agents, sweetening agents, preservative agents, and / or co-solvents or solubilisers.

[0040] In one embodiment the phenobarbital oral composition comprises or consists of a pharmaceutically effective amount of phenobarbital or a pharmaceutically acceptable salt thereof; at least one solvent selected from the group consisting of short, medium and / or long chain triglycerides; at least one co-solvent or solubiliser, and optionally one or more flavouring agents, sweetening agents and / or preservative agents.

[0041] In a preferred embodiment the phenobarbital composition consists of approximately 1% w / v of phenobarbital or a pharmaceutically acceptable salt thereof; approximately 0.5% w / v of raspberry flavour and made to up to approximately 100% w / v with medium chain triglycerides or Miglyol® (i.e. approx. 98.5% w / v). In a preferred embodiment the phenobarbital oral composition consists of approximately 1% w / v of phenobarbital or a pharmaceutically acceptable salt thereof; approximately 2% w / v of Transcutol® HP (Diethylene Glycol Monoethyl Ether); approximately 0.5% w / v of raspberry flavour, and made to up to approximately 100% w / v with medium chain triglycerides or Miglyol® (i.e. approx. 96.5% w / v).

[0042] In one embodiment the maximum concentration of phenobarbital reached in the patient’s blood (Cmax) after taking the composition according to the present invention (i.e. 50mg / 5ml) under fasting conditions is from about 600ng / ml to about 1500ng / ml, and further preferably is from about 640ng / ml to 1490ng / ml, and yet further preferably is 642.5ng / ml to 1485.2ng / ml.

[0043] Preferably the Cmax mean is 910.4ng / ml + / - 217ng / ml for the composition.

[0044] Preferably the Cmax for the composition is at least 600ng / ml, and further preferably is at least 640ng / ml, and yet further preferably is at least 642.5ng / ml.

[0045] In one embodiment the AUC0-72 after taking the composition according to the present invention (i.e. 50mg / 5ml) under fasting conditions is from about 27400ng.hr / ml to about 44400ng.hr / ml, and further preferably is from about 27450ng.hr / ml to about 44325ng.hr / ml, and yet further preferably from about 27478ng.hr / ml to about 44323ng.hr / ml.

[0046] Preferably the AUC mean is 36569.2ng.hr / ml + / -5243ng.hr / ml for the composition.

[0047] Preferably the AUC0-72 for the composition is at least 27400ng.hr / ml, and further preferably is at least 27450ng.hr / ml, and yet further preferably is at least 27478ng.hr / ml.

[0048] In one embodiment the Tmax range (hr) is about 0.3 to about 5.5, and further preferably is about 0.33 to about 5.00.

[0049] In one embodiment the 90% confidence interval (CI) for Cmax and / or AUC0-72 for the composition of the present invention was between 80-125% compared to the known (and medically approved) tablet form of phenobarbital, and further preferably was between 80-104% for Cmax and / or was between 95-103% for AUCo-

[0050] 72.

[0051] Preferably the Cmax and AU Co-72 are approximately proportional, and further preferably directly proportional, to dosage strength of the composition.

[0052] According to a second aspect of the present invention there is provided a method of manufacturing a phenobarbital composition suitable for oral administration in a human subject, said method including the steps of mixing a pharmaceutically effective amount of phenobarbital or a pharmaceutically acceptable salt thereof with at least one solvent selected from the group comprising or consisting of short, medium and / or long chain triglycerides.

[0053] Preferably the composition is a solution suitable for oral administration.

[0054] Preferably the short, medium and / or long chain triglycerides are added to the composition in an amount sufficient to make up the desired final volume of the solution / composition.

[0055] Preferably the method includes the step of adding one or more co-solvents or solubilisers to the composition.

[0056] Preferably the method includes the step of adding one or more flavouring agents to the composition.

[0057] In one embodiment the composition is preservative-free.

[0058] In one embodiment the method includes the step of adding one or more preservative agents to the composition.

[0059] Preferably the method includes the step of adding one or more sweetening agents to the composition.

[0060] Preferably the components of the composition are mixed together via any suitable mixing means, such as for example, a high shear mixing device. Preferably the at least one solvent or medium chain triglycerides are heated to approximately 40-80 degrees Celsius, and further preferably 60-65 degrees Celsius during at least the mixing step with the phenobarbital or salt thereof.

[0061] In one embodiment the phenobarbital or salt thereof is added to the at least one solvent or medium chain triglycerides and the mixture is mixed together.

[0062] In one embodiment the phenobarbital or salt thereof is added to the co-solvent or solubliser and is mixed together. Preferably the mixture of co-solvent / solubiliser and phenobarbital are then added to the at least one solvent or medium chain triglycerides. Further preferably the solvent or medium chain triglycerides ate heated to between 40-80 degrees Celsius and yet further preferably the temperature of the mixture is maintained at said temperature until all the components are dissolved into solution.

[0063] Preferably the one or more flavouring agents are added into the heated mixture.

[0064] Preferably the composition or solution undergoes a filtering step prior to bottling and / or use of the same using suitable filter means.

[0065] Preferably the filtering means is a polypropylene filter, and further preferably is a 40pm filter.

[0066] Preferably the composition is contained in an amber glass bottle for storage.

[0067] Preferably the composition is used as an anticonvulsant for the treatment in human subjects of any or any combination of epilepsy, seizures; generalised and partial seizures, generalised tonicoclonic and partial (cortical focal) seizures; as prophylaxis and treatment of febrile seizures; as a sedative for the relief of anxiety, tension and / or apprehension; as a hypnotic for the short term management of insomnia; as an anti- hyperblltrubinemic for the prevention and treatment of hyperbilirubinemia in neonates; or to lower bilirubin concentrations in patients with congenital non- hemoltyic unconjugated hyperbilirubinemia or chronic intrahepatic cholestasis. In one example the composition is not indicated for the treatment of absence seizures in human subjects. According to a further aspect of the present invention there is provided a method of using or manufacturing a phenobarbital composition for oral administration in a human subject according to claim 25.

[0068] Examples of formulations and methods of manufacture falling within the scope of the present invention will now be described below.

[0069] Example 1 Formulation

[0070] 2000L Batch Size

[0071] *1Based on a weight per ml of 0.944 g / ml

[0072] *2 Approximate amount of Medium Chain Triglycerides required to make to final weight. % w / v for the proposed formulation:

[0073] Example 1 - Method of manufacture according to one embodiment

[0074] 1. To a clean and dry main manufacturing vessel the Medium Chain Triglycerides or Miglyol® 812N (IOI Oleochemical GmbH, Germany) (A) were added and heated to 60 — 65°C and maintained at this temperature until the end of step 4.

[0075] 2. To a clean and completely dry separate stage vessel the Transcutol® HP (Diethylene Glycol Monoethyl Ether) was added (Gattefosse SAS, France) (B).

[0076] 3. To the separate stage vessel containing the Transcutol® HP, the Phenobarbital base (such as for example, Alkaloida Chemical Company ZRt, Hungary) (C) was added and mixed until dispersed using a high-shear mixer. NB: the Phenobarbital base may not fully dissolve at this stage.

[0077] 4. To the main manufacturing vessel, the dispersion produced at stage 3 was added and mixed until all the Phenobarbital base dissolved using a high-shear mixer. The temperature of the product was maintained between 60°C and 65°C for this stage until all the phenobarbital base was dissolved. (NB to ensure complete transfer of all the contents of the separate stage vessel, the vessel can be rinsed with several aliquots of fresh Medium Chain Triglycerides or Miglyol® 812N.) 5. To the main vessel the Raspberry Flavour (Ungerer Ltd, UK) (D) was added and mixed until dispersed using a high-shear mixer.

[0078] 6. To the main manufacturing vessel the Medium Chain Triglycerides or Miglyol® 812N (E) were added to make up to final weight of the solution and mixed until dispersed using a high-shear mixer.

[0079] 7. Mixing prior to filling is not essential for this solution product. Mixing prior to filling was evaluated for some example formulations and was deemed unnecessary but could be used.

[0080] 8. Prior to filling into bottles, the solution is filtered through filter means (such as for example, a 40 pm disposable polypropylene filter).

[0081] 9. The solution is filled into 150ml ambet glass bottles with a fill volume of 152 ± 2ml.

[0082] Example 2 Formulation

[0083] This formulation was made using the same methodology as for the Example 1 formulation. However, the Advantame® is mixed with the phenobarbital prior to mixing with the medium chain triglycerides.

[0084] Example 3 Formulation

[0085] This formulation was made using the same methodology as for the Example 1 formulation.

[0086] Example 4 Formulation

[0087] This formulation was made using the same methodology as for the Example 1 formulation. However, with the composition at the 25mg / 5 ml concentration, it was found that it was not necessary to include a co-solvent Transcutol HP in the method as the phenobarbital base was sufficiently soluble in the Miglyol without it. A co solvent could still be added to the 25mg / 5ml composition concentration if required though.

[0088] Solubility test examples for identifying suitable triglycerides

[0089] The above solubility tests were undertaken in order to identify possible examples of suitable triglycerides in which the phenobarbital would be soluble in. The following samples were prepared as saturated solutions whereby an excess of the active agent (phenobarbital) was mixed and heated with the triglyceride to dissolve as much as the active agent as possible. The saturated solution was kept in an 80 degrees Celsius oven overnight and then allowed to stand at room temperature (25 degrees) for a few days prior to analysis. It was found that the medium chain triglyceride or Miglyol® produced the best solubility of the active agent phenobarbital, although other triglycerides did provide sufficient solubility.

[0090] Results

[0091] It was found that a phenobarbital oral composition or solution according to the present invention using an oil based solvent rather than an aqueous excipient agent removed the risk of phenobarbital hydrates forming in the composition / solution over time. Phenobarbital was found in some instances not to be fully soluble at room temperature and at higher concentrations in the medium chain triglycerides for the product strength of 50mg / 5ml and so use of a co-solvent or solubiliser was preferable, such as for example, the use of Transcutol® HP. Transcutol® HP is a high purity Diethylene Glycol Mono Ethyl Ether that has low levels of impurity and so is suitable for human consumption. For lower concentrations 25mg / 5ml no solubiliser / co-solvent was required, as per Example 4. The use of a co-solvent or solubiliser in some formulations also appeared to maintain the stability of the solution for longer (i.e. it prevented the phenobarbital precipitating out to form crystals in the solution at around 6-9 months of storage).

[0092] The oil based formulation of the present invention was found to have significantiy improved stability with no precipitation out of phenobarbital, thereby providing the required amount of bioavailability of the active agent. Only minimal degradants were detected, even after storage at 40°C at 75% Relative Humidity (RH) for 12 months.

[0093] Stability tests undertaken in respect of the three different solution formulations were carried out at different time points (i.e. T= 0 months, T= 3 months, T=6 months, T=9months, T=12 months). The appearance of the solutions was monitored at 5°C refrigerator conditions, 30°C & 65%RH, and 40°C & 75% RH. All 4 formulations complied with the required appearance of the solution (i.e. colourless, pale yellow non-aqueous liquid) at 5°C at the measured time points.

[0094] At 30°C & 65%RH, the appearance of the solution was maintained at all time points for formulations 1, 2 ,3; and 4. The original starting amount of phenobarbital reduced by a maximum of 0.6% over the stability test, formulation 2 maintained the original starting amount of phenobarbital over the 12 months stability test, the original starting amount of phenobarbital in formulation 3 reduced by a maximum of 1.3% over the 12 months stability test. Total degradation products were less than 0.1% for formulation 2, and 0% for formulations 1 and 3; and all the 3 formulations complied with total aerobic microbial count, yeast and mould count and absence of E.coli for the duration of the test.

[0095] At 40°C & 75% RH, the appearance of the solution was maintained at all time points for formulations 1, 2 and 3; the original starting amount of phenobarbital over the 12 months stability test dropped by a maximum of 0.8% over all the tested batches. Total degradation products were less than 0.1% for formulations 1, 2 and 3 and all three formulations complied with total aerobic microbial count, yeast and mould count and absence of E.coli for the duration of the test.

[0096] Thus, in summary, all four formulations complied with the required stability parameters. Evidence of this is set out below.

[0097] In a mote detailed review of the stability data, formulation 3 which had the lower co-solvent / solubiliser amount of Transcutol® HP level at 1.1%, the removal of the sweetening agent Advantame® and increased 0.5% amount of Raspberry flavour showed no significant difference in Phenobarbital assay or levels of known or unknown degradants compared to formulation 2 containing 2% Transcutol®, 0.002% Advantame® and 0.2% Raspberry flavour.

[0098] Therefore, it was concluded that removing the Advantame®, lowering the Transcutol® HP from 2% to 1.1% and increasing the level of Raspberry Flavour from 0.25% to 0.5% had no effect on the stability of the Phenobarbital 50mg / 5ml Oral solution. The slight differences between formulation 2 and formulation 3 have no significant effect on the stability of the Phenobarbital oil-based solution.

[0099] For both formulations 2 and 3, there was no significant change in Phenobarbital assay and no increase in levels of known or unknown degradants seen across the 6 tested batches stored at 30°C / 65% RH or 40°C / 75% RH storage conditions throughout the trial. This indicates both formulations are very stable and nondegrading.

[0100] The stability data for formulation 1 showed no significant difference to the stability data seen for both formulations 2 and 3. Therefore, the stability of all three formulations was not significantly different.

[0101] There has been no significant change (significant change is defined as a 5% change in Assay from its initial value) or variability with the accelerated data (40°C / 75%RH) up to 9 months for any of the tested batches or for the long term (30°C / 65%RH) teal time data at 18 months. ICH Q1E guidelines state that the proposed retest period or shelflife can be up to twice but should be no more than 12 months beyond the period covered by the long-term data. On this basis the product can be given a 30-month shelf life based on long term data being well within specification at 18 months and accelerated stability data being well within specification at 9 months timepoint when stored at 40°C / 75% RH.

[0102] Thus, the oil based phenobarbital oral solution of the present invention is a stable product having a shelf life of up to 30 months.

[0103] Bioequivalence Study

[0104] An open-label, balanced, randomized, single oral dose, two-treatment (Example 1 liquid formulation vs known tablet brand product), two-sequence (different volunteers got products at different times), two period, two-way crossover, comparative bioavailability study of Phenobarbital oral solution 50mg / 5mL (3mL dose equivalent to 30mg) (Example 1 previously described) (Test Treatment T) of Rosemont Pharmaceuticals Limited, United Kingdom with Phenobarbital 30 mg Tablets (Reference Treatment R) of Clonmel Healthcare Ltd Waterford Road Clonmel, Co. Tipperary Ireland in normal healthy, adult, human male study participants under fasting conditions.

[0105] Pharmacokinetic Results:

[0106] The results of the bioequivalence study are shown in Table 1 below and with reference to figure 1, wherein nominal hours post dose treatment is shown on the X-axis vs the Mean Plasma Concentration (ng / ml) of the drug active phenobarbital in the patient’s blood is shown on the Y-axis.

[0107] Table 1: Arithmetic Mean of Pharmacokinetic Parameters of Phenobarbital

[0108] Where maximum concentration reached in the patient’s blood;

[0109] AUCO-72 = Area under the curve 0-72hours

[0110] (hr) = time to reach maximum concentration

[0111] N= number of patients

[0112] Statistical Results

[0113] Table 2a: Statistical Results of Assessment of comparative bio availability of Phenobarbital under fasting conditions for Phenobarbital oral solution 50mg / 5mL (3mL dose equivalent to 30mg) (Test Treatment T) with Phenobarbital 30 mg Tablets (Reference Treatment R) (N = 14).

[0114] The Geometric Mean (GM) Ratio with 90% Confidence Interval (CI) of Ratio estimates of Cmaxand AUC0-72 values of the Phenobarbital oral solution 50mg / 5mL (3mL dose equivalent to 30mg) (Test Treatment T) over those of the Phenobarbital 30 mg Tablets (Reference Treatment R) were 91.04 (80.22, 103.32) and 99.02 (95.86, 102.28) respectively.

[0115] The 90% CI for Cmax and AUCo 72 were within 80.00-125.00% range.

[0116] Based on above mentioned criteria, it was concluded that the Test formulations Phenobarbital oral solution 50mg / 5mL (3mL dose equivalent to 30mg) (Example 1 formulation) was bioequivalent to Reference formulation Phenobarbital 30 mg Tablets in terms of rate and extent of absorption under fasting conditions.

[0117] Thus, it was found that the liquid formulations of the present invention had the same or similar bio availability as the equivalent branded tablet formulations. This is unexpected and surprising given that the drug active (i.e. phenobarbital) was dissolved in an oil based vehicle.

[0118] Table 2b - Pharmacokinetic Parameters of Phenobarbital Formulation Stability Studies

[0119] Stability Studies for Example 1 Formulation

[0120] Formulation Example 1 - 5°C Data - 200L Clinical Trial batch

[0121] The stability of a formulation according to Example 1 was tested at 5°C + / - 3°C at time points 0, 3, 6, 9, 12, 18 & 24 months, as shown in Table 3. The appearance of the solution was assessed at each time point. If the solution was maintained at the required specification (i.e. being a colourless to pale yellow non-aqueous liquid), then the stability of the formulation was considered to comply.

[0122] Table 3

[0123] The stability of a formulation according to Example 1 was tested at 30°C, 65% relative humidity (RH) at time points 0, 3, 6, 9, 12, 18 & 24 months, as shown in Table 4.

[0124] Table 4

[0125] ND = Not Detected NR =Not Requited

[0126] Microbiology TAMC = total aerobic microbial count

[0127] Microbiology TYMC = total combined yeasts and molds count

[0128] CPU = Number of colony forming units

[0129] The stability of a formulation according to Example 1 was tested at 40°C, 75% relative humidity (RH) at time points 0, 3, 6, 9 & 12 months, as shown in Table 5.

[0130] Table 5

[0131] ND — Not Detected NR — Not Required

[0132] The stability data shows that a formulation according to Example 1 remains stable for at least 12 months. There is no significant decrease in Phenobarbital assay across all storage conditions and there is no increase in levels of total degradation products seen for all storage conditions. Samples stored at 40C / 75% RH for up to 12 months show no significant decrease in phenobarbital assay or any increase in levels of total degradants. Thus, this shows that the Phenobarbital 50mg / 5ml Oral solution is very stable.

[0133] Stability Studies for Example 2 Formulation

[0134] Formulation Example 2 — 5°C Data

[0135] The stability of a formulation according to Example 2 was tested at 5°C + / - 3°C at time points 0, 3, 6, 9 & 12 months, as shown in Table 6. The appearance of the solution was assessed at each time point. If the solution was maintained at the required specification (ie. being a colourless to pale yellow non-aqueous liquid), then the stability of the formulation was considered to comply. Table 6

[0136] The stability of a formulation according to Example 2 was tested at 30°C, 65% relative humidity (RH) at time points 0, 3, 6, 9 & 12 months, as shown in Table 7.

[0137] Table 7

[0138] The stability of a formulation according to Example 2 was tested at 40°C, 75% relative humidity (RH) at time points 0, 3, 6, 9 & 12 months, as shown in Table 8.

[0139] Table 8

[0140] Stability Studies for Example 3 Formulation

[0141] Formulation Example 3 - 5°C Data

[0142] The stability of a formulation according to Example 3 was tested at 5°C + / - 3°C at time points 0, 3, 6, 9 & 18 months, as shown in Table 9. The appearance of the solution was assessed at each time point. If the solution was maintained at the required specification (i.e. being a colourless to pale yellow non-aqueous liquid), then the stability of the formulation was considered to comply.

[0143] Table 9 The stability of a formulation according to Example 3 was tested at 30°C, 65% relative humidity (RH) at time points 0?3, 6, 9 & 18 months, as shown in Table 10.

[0144] Table 10

[0145] The stability of a formulation according to Example 3 was tested at 40°C, 75% relative humidity (RH) at time points 0, 3, 6 & 9months, as shown in Table 11.

[0146] Table 11

[0147]

[0148] References

[0149] [1] https: / / www.ncbi.nlm.nih.gov / books / NBK532277 / #: ~ :text=Phenobarbital%20i s%20a%20member%20of5addressing%20benzodiazepine%20and%20alcohol%20 withdrawal

Claims

Claims1. A phenobarbital composition suitable for oral administration tn a human subject, said composition comprising a pharmaceutically effective amount of phenobarbital or a salt thereof; and at least one solvent selected from the group comprising or consisting of short, medium and / or long chain triglycerides.

2. The phenobarbital composition according to claim 1, wherein the triglycerides include any or any combination of Miglyol®, Miglyol® 812N, fractionated medium chain coconut fatty acids, CAS 73398-61-5, Caprylic / Capric Triglyceride, Miglyol® 810N, coconut oil, palm kernel oil, corn oil, soyabean oil, cod liver oil, safflower oil, almond oil, soybean oil, peanut oil, plant derived oil, rapeseed oil, flaxseed oil, cottonseed oil, sesame oil, sunflower oil, walnut oil, ground nut oil, or olive oil.

3. The phenobarbital composition according to any preceding claim, wherein the at least one solvent or the medium chain triglycerides is used in an amount equal to or greater than approximately 75% w / v of the composition, equal to or greater than approximately 80% w / v of the composition, equal to or greater than approximately 85% w / v of the composition, equal to or greater than approximately 90% w / v of the composition, equal to or greater than approximately 95% w / v of the composition; between approximately 80% w / v - 99% w / v of the composition, between approximately 96% w / v — 99% w / v of the composition; approximately 96.5%w / v of the composition; approximately 98.5% w / v of the composition, or approximately 99% w / v of the composition.

4. The phenobarbital composition according to any preceding claim, wherein the phenobarbital used in the composition is phenobarbital base and / or phenobarbital sodium.

5. The phenobarbital composition according to claim 1, wherein the phenobarbital base or salt thereof is used in an amount of approximately 1% w / v or less of the composition; or is used in an amount of approximately 0.5% w / v or less of the composition.

6. The phenobarbital composition according to any preceding claim, wherein the phenobarbital or salt thereof is used in an amount of 50mg / 5ml or 25mg / 5ml of the composition.

7. The phenobarbital composition according to any preceding claim, wherein the composition contains no co-solvent or solubiliser.

8. The phenobarbital composition according to any of claims 1-6, wherein the composition includes at least one co-solvent or solubiliser.

9. The phenobarbital composition according to claim 8, wherein the at least one co-solvent or solubiliser includes or consists of Diethylene Glycol Monoethyl Ether, CAS111-90-0, Transcutol® or a Transcutol® High Purity (HP) grade.

10. The phenobarbital composition according to claim 8, wherein the at least one co-solvent or solubiliser includes any or any combination of Diethylene Glycol Monoethyl Ether, CAS111-90-0, Transcutol® HP, Transcutol®, Ethanol, Propylene Glycol, Caproyl® 90, Propylene Glycol Monocaprylate, CAS 31565-12-5, contains propylene glycol esters of caprylic acid, one or more sugar alcohols, glycerol, sorbitol or mannitol.

11. The phenobarbital composition according to any of claims 8-10, wherein the at least one co-solvent or solubiliser is used in an amount of approximately 1% w / v - 20% w / v of the composition; is used in an amount of 5% w / v or less of the composition; or is used in an amount of approximately 2% w / v + / -0.5% w / v of the composition.

12. The phenobarbital composition according to claim 8, wherein the at least one co-solvent or solubiliser is Transcutol® or Transcutol® HP (Diethylene Glycol Monoethyl Ether or CASH 1-90-0) and is used in an amount of approximately 2% w / v of the composition.

13. The phenobarbital composition according to any preceding claim, wherein the composition includes at least one flavouring agent.

14. The phenobarbital composition according to claim 13, wherein the at least one flavouring agent is used in an amount of approximately 0.1% w / v -1.5 % w / v of the composition, or approximately 0.2-0.5% w / v of the composition.

15. The phenobarbital composition according to any preceding claim, wherein the composition is preservative-free.

16. The phenobarbital composition according to any of claims 1-14, wherein the composition includes one or more preservative agents.

17. The phenobarbital composition according to claim 16, wherein the one or more preservative agents contained in the composition are used in an amount of approximately 1-20% w / v of the composition.

18. The phenobarbital composition according to any preceding claim, wherein the composition includes one or more sweetening agents.

19. The phenobarbital composition according to claim 18, wherein the one or more sweetening agents include any or any combination of Saccharin base, Advantame®, Neotame®, N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L- a-aspartyl]-L-phenylalanine 1 -methyl ester monohydrate, CAS 714229-20-6, an N-substituted derivative of aspartame, L-phenylalanine, N-[N-(3,3-dimethylbutyl) L-a-aspartyl]-,l -methyl ester, CAS 165450-17-9, or an aspartame analog.

20. The phenobarbital composition according to claims 18 or 19, wherein the one or more sweetening agents contained in the composition are used in an amount of approximately 0.01-2% w / v of the composition.

21. The phenobarbital composition according to claim 1, comprising or consisting of a pharmaceutically effective amount of phenobarbital or a pharmaceutically acceptable salt thereof; at least one solvent selected from the group consisting of short, medium and / or long chain triglycerides; and optionally one or more flavouring agents, preservative agents, sweetening agents and / or co-solvents or solubilisers.

22. The phenobarbital composition according to claim 1, including or consisting of approximately 1% w / v of phenobarbital base or a salt thereof, approximately 97% w / v medium chain triglycerides, and approximately 2% w / v of Transcutol® HP (Diethylene Glycol Monoethyl Ether), and optionally at least one flavouring agent; or including or consisting of approximately 0.5%w / v of phenobarbital base or a salt thereof, approximately 99-99.5%w / v medium chain triglycerides, and optionally 0.5%w / v flavouring agent.

23. The phenobarbital composition according to claim 1, consisting of approximately 1% w / v of phenobarbital or a pharmaceutically acceptable salt thereof; approximately 2% w / v of Transcutol® HP (Diethylene Glycol Monoethyl Ether); approximately 0.5% w / v of raspberry flavour, and made to up to approximately 100% w / v with medium chain triglycerides or Miglyol®.

24. The phenobarbital composition according to any preceding claim, wherein under fasting conditions provides a Cmax from about 600ng / ml to about 1500ng / ml and / or an AUG 0 72 from about 27400ng.hr / ml to about 44400ng.hr / ml.

25. A method of using or manufacturing a phenobarbital composition according to claim 1 for oral administration in a human subject for the treatment of any or any combination of epilepsy, seizures; generalised and partial seizures, generalised tonicoclonic and partial (cortical focal) seizures; as prophylaxis and treatment of febrile seizures; as a sedative for the relief of anxiety, tension and / or apprehension; as a hypnotic for the short term management of insomnia; as an anti-hyp erbilirubinemic for the prevention and treatment of hyperbilirubinemia in neonates; or to lower bilirubin concentrations in patients with congenital non-hemoltyic unconjugated hyperbilirubinemia or chronic mtrahepatic cholestasis.

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