GB2617419A

GB2617419A - Stable composition of chloral hydrate

Info

Publication number: GB2617419A
Application number: GB2210518.3A
Authority: GB
Inventors: Mcquillan James
Original assignee: Atnahs Pharma UK Ltd
Current assignee: Atnahs Pharma UK Ltd
Priority date: 2022-07-18
Filing date: 2022-07-18
Publication date: 2023-10-11
Also published as: WO2023139294A1; GB2614972B; GB2614972A; GB202210518D0

Abstract

A chloral hydrate solution comprising chloral hydrate in an amount ranging from 20 mg/ml to 100 mg/ml and one or more pharmaceutically acceptable excipients, wherein the solution has a pH of 3.2 to 4.5 is provided. The solution is stable over a period of at least 12 months, such that the solution contains no more than 300 ppm of chloroform, no more than 800 ppm of formic acid and no more than 100 ppm of monochloroacetaldehyde. The pharmaceutically acceptable excipient may include one or more of a buffer, a pH adjusting agent, diluent, suspending agent, sweetener, flavouring agent, and antimicrobial agent. The buffer may be selected from citrate, acetate, phosphate, and mixtures thereof, preferably a mixture of citric acid and sodium citrate. The therapeutic use of the solution in sedating a subject is provided. A method of preparing the chloral hydrate solution comprising mixing the chloral hydrate with one or more pharmaceutically acceptable excipients in an aqueous solution is provided. An example composition comprises chloral hydrate, citric acid, sodium citrate, glucose, glycerol, sodium benzoate, saccharin sodium, essence of passion fruit and water. The solution may comprise chloral hydrate at a strength of 500 mg/5ml or 143 mg/5ml.

Description

STABLE COMPOSITION OF CHLORAL HYDRATE

FIELD OF THE INVENTION

The present invention relates to a stable composition of chloral hydrate and particularly, although not exclusively, to its use as an oral solution in the short-term treatment of severe insomnia and for sedation in pediatric patients. The composition is stable over its shelf life and has low levels of chloroform and other impurities at the end of shelf life.

BACKGROUND OF THE INVENTION

Chloral Hydrate Oral Solution is indicated in adults for the short-term treatment (maximum 2 weeks) of severe insomnia which is interfering with normal daily life and where other therapies (behavioural and pharmacologic) have failed. Chloral Hydrate Oral Solution is typically used as an adjunct to non-pharmacological therapies. Chloral Hydrate Oral Solution is also indicated for the short-term treatment (maximum 2 weeks) of severe insomnia in children and adolescents with suspected or definite neurodevelopmental disorder, when the insomnia is interfering with normal daily life and other therapies (behavioural and pharmacologic) have failed. The treatment is used as an adjunct to behavioural therapy and sleep hygiene management in children. Chloral hydrate has been used for a great many years as a sedative/hypnotic drug in human and veterinary medicine. The metabolite (trichloroethanol) is responsible for the pharmacological effect. The proposed mechanisms for the depression of the central nervous system include potentiating the function of GABAA receptors, inhibition of excitatory amino acid-activated currents mediated by N-methyl-D-aspartate, and allosteric modulation of the 5-hydroxytryptamine 3 receptor-mediated depolarization of the vagus nerve.

Chloral hydrate oral solution was first approved several years ago, but faced issues with respect to stability. It is known to undergo degradation upon storage, leading to formation of chloroform, which is a known carcinogen. It has been observed that while previously approved chloral hydrate oral solutions had an authorized shelf life of 18 months, that was reduced to 6 months in view of the amount of chloroform that was formed, despite storing the product at a temperature below 25 °C. Chloral hydrate solutions have also been available, and continue to remain available, as compounded medications, i.e. an oral solution of chloral hydrate is prepared by compounding pharmacies that are present in a hospital setting, or that provide the compounded product upon request to hospitals. While these compounded products have been touted to have the advantage of being available immediately upon request, and can be compounded at the desired concentration based on the need of the patient, what is detrimental is that these are possibly only tested as per the monograph requirements in the British Pharmacopoeia, i.e. only for assay of chloral hydrate. Thus, while the compounded chloral hydrate solution may have a "best before" date, there is no testing done to establish the content of chloroform and/or formic acid in the solution. Mostly, the compounded solutions are to be used within days of manufacturing. But in the absence of complete testing, even bulk solutions that test for only the assay of the solution (but do not test chloroform and formic acid), pose a risk in view of the degradation that may happen due to improper storage, such as at a higher temperature. Further, compounded products have the additional risk of being microbially contaminated if not prepared under GMP conditions. Thus, compounded chloral hydrate solutions have known disadvantages of low shelf life and untested levels of impurities, some of which may be carcinogenic, apart from the fact that there may be errors in dosing that may arise due to inefficient compounding. The health hazard from such use needs to be addressed on a high priority.

Luknitskii (Chemical Reviews, Vol 75, No 3, "The Chemistry of Chloral", 259-289, Jun 1975) reported that the decomposition of chloral hydrate under the influence of strong alkalies, to form chloroform and formates, is common knowledge. The author reports that in spite of the stability of chloral hydrate, its solutions are not stable. On the one hand, this is connected with the hydration equilibrium; some researchers have recorded decomposition with elimination of water. On the other hand, chloral hydrate decomposes in neutral, acidic, and basic solutions. "Neutral" aqueous solutions are not stable for a long time; after 15 weeks the pH decreases from 6.72 to 4.75-2.33 (more in light and on cooling). UV irradiation accelerates this process; the pH decreases from 6.25 to 1.6 in 10 hr. The large decrease in pH of aqueous solutions of chloral hydrate on standing is the result of CCb-group destruction, with HC1 formation. The instability of chloral hydrate in alkaline solutions is well known. But most investigators have taken into account only the heterolysis of C-C bonds or have made their studies at such pH and temperature ranges that the other reaction -hydrolysis of the trichloromethyl group without CC bond rupture -has been repressed almost completely.

Bustos-Fierro et al ("Stability evaluation of 7% chloral hydrate syrup contained in mono and multi-dose bottles under room and refrigeration condition", Farmacia Flospitalaria, 2013; 37(1):4-9) evaluates the stability of an extemporaneously prepared 7% chloral hydrate syrup under different conditions of storage and dispensing. The physical, chemical and microbiological stability was evaluated for 1.80 days. The chemical stability of the formulation was defined as not less than 95% of the initial drug concentration remaining in the samples and a pH value not less than 2.05. the absence of visible particulate matter, or colour and/or odour changes and the compliance with microbiological attributes of non-sterile pharmaceutical products. The authors concluded that extemporaneously compounded 7% chloral hydrate syrup was stable for at least 180 days when stored in mono--or multi--dose light-resistant glass containers at room temperature and under refrigeration, while the pH was maintained between 2.97 to 3.09. However, it must be noted that calculations indicate that 500mg/5m1 solution of chloral hydrate may contain as high as 3800 ppm of chloroform if the assay degrades by 5%.

So a solution that has assay meeting the "not less than 95 specification may still contain a very large amount of chloroform. As such, assay of chloral hydrate is meaningless as regards denoting the content of chloroform, or overall stability of the solution.

Thean et al ("Stability of extemporaneously compounded chloral hydrate oral solution", Vol 4 No 1(2018) Malaysian Journal of Pharmacy) studied the stability of Chloral Hydrate 40 mg per ml oral solution formulated in X-temp Oral Suspension System in order to select proper storage conditions and establish beyond-use date. X-temp is an oral, flavoured sugar-free extemporaneous compounding vehicle to assist in the preparation of extemporaneous dosage forms. To be considered stable, the preparation had to retain a minimum of 90% of its initial drug dose and a pH value between 3.8 and 4.8. The analytic results indicated that the chloral hydrate content in all samples assayed was above 99% throughout the 180 days period at 5 °C and 30 °C. During the study, little or no chloral hydrate loss occurred in the samples for both storage conditions over 180 days. The authors reported that Chloral hydrate is easily decomposed in alkaline solution yielding mostly chloroform and formic acid. The stability of the preparation is due to the compatibility of chloral hydrate with the X-Temp vehicle and al so the protective nature of the amber plastic container which prevents light degradation. The X-temp vehicle has an average pH of 4.1 (slightly acidic) and is buffered with the Citric Acid -Monosodium Phosphate buffering system. The nature of the X-temp vehicle ensures that the pH of the chloral hydrate solution remains slightly acidic and constant which is favourable towards the stability of chloral hydrate. The pH remained within the range of 3.8 to 4.1 and the assay was stable, which suggests minimal or no chemical degradation throughout the study period of 180 days. However, nothing in this article teaches or suggests means for obtaining a chloral hydrate solution that has a longer shelf life, such as up to 24 months.

Some efforts have been made to stabilize chloral hydrate solutions. CN 112656758 discloses a stable chloral hydrate syrup comprising chloral hydrate, cane sugar and water, wherein the mass volume concentration of chloral hydrate is 10%, and the pH value of the chloral hydrate syrup is 2.3-3.0. The inventors state that stability of chloral hydrate is very poor, and is greatly influenced by temperature, illumination and solution pH value. The patent application states that chloral hydrate syrup prepared in hospitals has no systematic impurity research, and particularly, research reports on generated 5-hydroxymethylfurfural (degradation product of the syrup in the composition) and toxic chloroform (trichloromethane) are not carried out. The applicants conducted systematic studies on the formulation of chloral hydrate syrups and found that the stability of chloral hydrate decreased with increasing acidity of the solution, with chloral hydrate degrading to toxic chloroform at higher pH, whereas sucrose in syrup is converted to toxic 5-hydroxymethylfurfural. Therefore, the control range of the pH of the chloral hydrate syrup was stated to be the key for determining the quality of the chloral hydrate syrup. The publication states that when the pH value of the chloral hydrate syrup is between 2.3 to 3.0, the long-term stability is good, and the chloroform (not more than 0.06%) and the 5-hydroxymethylfurfural (not more than 0.5%) can be controlled within the allowable range of the pharmacopoeia. The publication also provides comparison of the stability of their composition with two compounded preparations of chloral hydrate available from local hospitals, both of which were 10% chloral hydrate oral liquids with pH 3.84 and pH 3.46, respectively. All three products were stored at 60 °C for 30 days and at 40 °C for 30 days, and stability was investigated by testing the amount of chloroform formed. The publication reports that while the compounded hospital products degraded significantly to form more than 0.4% of chloroform, the chloral hydrate syrup containing glycerol and having a pH of 2.3 to 3.0 was found to have chloroform content below 0.06%. However, there is no disclosure on the shelf life of the chloral hydrate composition, and certainly no detailing on how to obtain a product that is stable for up to 24 months. This publication in fact teaches that higher pH, such as that of the compounded hospital products, provides an unstable product.

CN 110151687 discloses a chloral hydrate solution concentrate, which comprises chloral hydrate, a pharmaceutically acceptable acid and water, wherein the mass concentration of the chloral hydrate is 40-80%, and the pH value of the chloral hydrate solution is preferably between pH 1.0 to pH 2.9. From the results shown in figure 1 of this publication, it is understood that the amount of chloroform increases as the pH of the chloral hydrate solution increases. When the pH of the chloral hydrate solution is greater than 2.9, the amount of chloroform produced was shown to increase sharply with an increase in the pH of the chloral hydrate solution. Therefore, the publication teaches that a lower pH is advantageous for improving the stability of chloral hydrate, and the product has been reported to have a shelf life of 24 months, wherein the amount of chloroform in the product does not exceed 0.06%. However, such a chloral hydrate solution having lower pH value and higher concentration was reported to have poor taste and certain irritation, thereby making it unsuitable for oral administration.

Both the above Chinese publications refer to literature reports that teach use of an inclusion compound like beta-cyclodextrin with chloral hydrate oral solution to improve stability. However, the effective period or shelf life of the product was reported to be prolonged to only 46.63 days. Similarly, other references reported chloral hydrate syrup with pH of 4.21 to 4.77, but no reported improvement in shelf life of the product.

There is therefore a need for a stable oral solution of chloral hydrate that is stable over a longer period of time. The present invention has been devised in light of these considerations.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/m1 to about 100mg/ml and one or more pharmaceutically acceptable excipients; wherein the solution has a pH of about 3.2 to about 4.5.

In some embodiments, the present invention provides a chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/m1 to about 100mg/m1 and one or more pharmaceutically acceptable excipients; wherein the solution has a pH of about 3.2 to about 4.5; such that the solution has no more than 300 ppm of chloroform, no more than 800 ppm of formic acid, and no more than 100 ppm of monochloroacetaldehyde, when stored at 25 °C, 60% relative humidity for 9 months.

Suitably, the chloral hydrate solution is an oral chloral hydrate solution In some embodiments, the solution has a pH of about 3.7 to about 4.5. In some embodiments, the solution has a pH of about 4.1 to about 4.4.

In some embodiments, the solution has a pH of 3.2 to 4.5. In some embodiments, the solution has a pH of 3.7 to 4.5. In some embodiments, the solution has a pH of 4.1 to 4.4.

In some embodiments, the chloral hydrate solution comprises one pharmaceutically acceptable excipient. In some embodiments, the chloral hydrate solution comprises more than one pharmaceutically acceptable excipient. In some embodiments, the chloral hydrate solution comprises one, two, three, four, five six, seven, eight or more pharmaceutically acceptable excipients.

In some embodiments, the one or more pharmaceutically acceptable excipients include one or more of a buffer, a pH adjusting agent, diluent, suspending agent, sweetener, flavouring agent and antimicrobial agent.

In some embodiments, the chloral hydrate solution comprises either a buffer or a pH adjusting agent.

In some embodiments, the chloral hydrate solution comprises a buffer. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of about 3.2 and about 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of 3.2 and 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of about 3.7 and about 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of 3.7 and 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of about 4.1 and about 4.4. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of 4.1 and 4.4.

In some embodiments, the chloral hydrate solution comprises a buffer and one or more further pharmaceutically acceptable excipients, optionally selected from a diluent, suspending agent, sweetener, flavouring agent and antimicrobial agent. Preferably, the buffer is selected from citrate, acetate, phosphate and mixtures thereof In some embodiments, the buffer is a mixture of citric acid and sodium citrate, preferably in a ratio of about 60:40 to about 90:10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 65:35 to about 90:10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 85:15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 65:35 to about 85:15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 82:18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 65:35 to about 82:18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 70:30 to about 82:18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 82:18 by weight.

In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 90:10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 65:35 to 90:10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 85:15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 65:35 to 85:15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 82:18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 65:35 to 82:18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 70:30 to 82:18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 82:18 by weight.

In some embodiments, the chloral hydrate solution comprises a pH adjusting agent. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of about 3.2 to about 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of 3.2 to 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of about 3.7 to about 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of 3.7 to 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution is has a pH of about 4.1 to about 4.4. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of 4.1 to 4.4.

In some embodiments, the chloral hydrate solution comprises a pH adjusting agent and one or more further pharmaceutically acceptable excipients, optionally selected from a diluent, suspending agent, sweetener, flavouring agent and antimicrobial agent. Preferably, the buffer is selected from citrate, acetate, phosphate and mixtures thereof In some embodiments, the pH adjusting agent is selected from hydrochloric acid, a water soluble organic acid and mixtures thereof In some embodiments, the pH adjusting agent is hydrochloric acid. In some embodiments, the pH adjusting agent is a water soluble organic acid. In some embodiments, the pH adjusting agent is a mixture of water soluble organic acids. In some embodiments, the pH adjusting agent is a mixture of hydrochloric acid and one or more water soluble organic acids.

In some embodiments, the chloral hydrate solution comprises a diluent. Preferably, the diluent is selected from water, alcohol, liquid glucose, syrup, sorbitol, glycerol, propylene glycol, polyethylene glycol and mixtures thereof In some embodiments, the chloral hydrate solution comprises a suspending agent.

In some embodiments, the chloral hydrate solution comprises a sweetener. Preferably, the sweetener is selected from agave nectar, brown rice syrup, hydrogenated glucose syrup, date sugar, honey, molasses, blackstrap molasses, sorghum syrup, stevia, maple syrup, birch syrup, yacon syrup, lucuma powder, coconut sugar, erythritol, maltitol, mannitol, sorbitol, xylitol, isomalt crystals, lactitol, maltitol, acesulfame, advantame, alitame, allulose, aspartame, neotame, saccharin, sodium saccharin, sucralose, acesulfame potassium, tagatose, thaumatin, stevioside and mixtures thereof In some embodiments, the chloral hydrate solution comprises a flavouring agent Preferably, the flavouring agent is selected from almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, mango, grape, grapefruit, guava, hop, lemon, licorice, lime, elderberry, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pomegranate, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, winter green, tutti-frutti, bubblegum and mixtures thereof.

In some embodiments, the chloral hydrate solution comprises an antimicrobial agent. Preferably, the antimicrobial agent is selected from benzoic acid, methyl paraben, propyl paraben, butyl paraben, sorbic acid and their pharmaceutically acceptable salts, and mixtures thereof In some embodiments, the choral hydrate solution has no more than 300 ppm of chloroform, no more than 800 ppm of formic acid and no more than 100 ppm of monochloroacetaldehyde for 24 months when stored below 25 °C.

In some embodiments, the chloral hydrate is present in an amount of 450 to 550 mg/5m1, more preferably 475 to 525 mg/5m1, even more preferably 490 to 510 mg/5m1, and most preferably about 500mg/5m1. In some embodiments, the chloral hydrate is present in an amount of 500mg/5m1 In other embodiments, the chloral hydrate is present in amount of 120 to 160 mg/5m1, more preferably 130 to 155 mg/5m1, even more preferably 135 to 150 mg/5m1, and most preferably about 143 mg/5m1.

In a second aspect, the present invention provides the chloral hydrate solution of the first aspect for use in a method of treatment of the human or animal body. The second aspect also provides the use of the chloral hydrate solution of the first aspect in a method of treatment of the human or animal body.

In a third aspect, the present invention provides the chloral hydrate solution of the first aspect for use in the treatment of insomnia. The third aspect also provides the use of the chloral hydrate solution of the first aspect in a method of treating insomnia. Also provided is the use of the chloral hydrate solution of the first aspect in the manufacture of a medicament for the treatment of insomnia.

In a fourth aspect, the present invention provides the chloral hydrate solution of the first aspect for use in a method of sedating a subject. The fourth aspect also provides the use of the chloral hydrate solution of the first aspect in a method of sedating a subject. Also provided is the use of the chloral hydrate solution of the first aspect in the manufacture of a medicament for sedating a subject Preferably the subject is a pediatric patient In the second, third and fourth aspects of the invention, the chloral hydrate solution is preferably administered orally.

In a fifth aspect, the present invention provides a method of preparing the chloral hydrate solution of the first aspect, comprising mixing the chloral hydrate with the one or more pharmaceutically acceptable excipients in an aqueous solution.

The invention includes the combination of the aspects and preferred features described, except where such a combination is clearly impermissible or expressly avoided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable oral chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/m1 to about 100mg/m1 and pharmaceutically acceptable excipients, wherein the pH of the solution ranges from about 3.2 to about 4.5, and wherein the solution has a shelf life of at least 24 months, such that the solution has no more than 300ppm of chloroform and no more than 800ppm of formic acid, when stored below 25°C.

Chloral Hydrate 500mg/5m1 Oral Solution of the present invention is to be administered as a single daily dose, between 15 to 30 minutes before bedtime with water or milk. The usual dose in adults is 430-860 mg (4.3-8.6 ml of the 500mg/5m1 strength). Higher doses should not exceed a maximum of 2 g chloral hydrate (20 ml of the 500mg/5m1 strength) per dose. In children 12 years and over, the usual dose is 430-860 mg (4.3-8.6 ml of the 500mg/5m1 strength). Higher doses should not exceed a maximum of 2 g chloral hydrate (20 ml of the 500mg/5m1 strength) per dose. In children between 2 and 11 years of age, the dose is 30-50 mg/kg (0.3-0.5 ml/kg of the 500mg/5m1 strength) of bodyweight. The dose should not exceed 1 g chloral hydrate (10 ml of the 500mg/5m1 strength) per dose.

Scheme 1 shows a simplified chemical equation for the degradation of chloral hydrate to form equimolar amounts of chloroform and formic acid.

OH H20 0 OH CI CI H./1^OH

CI CI

CI

Chloral hydrate Chloroform Formic acid Scheme 1 The exact mechanism is still not fully understood in the scientific literature, although the formation of chloroform and formic acid is well established. This is essentially a hydrolysis degradation mechanism, i.e. the addition of a water molecule across the carbon-carbon backbone splits the chloral hydrate into the equimolar, individual components of chloroform and formic acid. Like all hydrolytic degradation processes, the rate of this reaction is also dependent on the physical and chemical environment in which the chloral hydrate is present.

The present inventors have previously worked on a chloral hydrate solution of strength 143mg/5m1, which was commercially available. A review of the development work performed on the Chloral hydrate 143ms/5 ml oral solution highlighted that chloral hydrate API itself has a natural acidic pH (the European Pharmacopoeia monograph highlights an aqueous solution pH of 3.5 -5.5 for a 10 % w/v solution of the API dissolved in carbon dioxide free-water). The chloral hydrate API is freely soluble in water, but it is susceptible to a degradation pathway leading to formation of equimolar quantities of chloroform and formic acid. Hence, the natural pH of the API dissolved in water actually catalyses the degradation mechanism. The aqueous based oral solution of chloral hydrate is thus exposed to a self-perpetuating degradation process. Upon manufacture of the oral solution, when the API is dissolved in water, the hydrolysis degradation mechanism is initiated. The thermal conditions were found to enhance the degradation mechanism pathway but do not initiate the degradation itself, as water is the primary initiator.

The original formulation of 143mg/5m1 oral solution was manufactured as an unbuffered formulation. The natural pH of this unbuffered oral solution was about 6.1-6.2 upon manufacture, and the rate of degradation was observed to be fast at this particular pH. As the oral solution continued to degrade, the amount of formic acid increased. There was a subsequent drop in pH of the solution, and eventually the rate of chloroform formation was observed to have decreased. Therefore, the conclusion was that the more acidic the oral solution, the better the observed stability, in terms of the chloroform formation. pH development trial batches of the 143mg/5m1 formulation were conducted which showed that the addition of an acidic buffer system stabilised the finished product, leading to a reduced rate of chloroform formation. The solution was reformulated by addition of a combination of citric acid and sodium citrate in a 60:40 ratio and adjusting the pH between 4.5 and 6.5. This solution was commercialized with a shelf life of one year (unopened bottle) and 28 days (opened bottle), when stored below 25 °C. However, it was later discovered that the amount of chloroform increased in the solution such that the levels were much higher than the ICH residual solvent limit for chloroform of 300 ppm. Accordingly, the shelf life of the 143mg/5m1 oral solution had to be revised and reduced to 6 months (unopened bottle) and 28 days (opened bottle), when stored below 25 °C. The root cause for this increased degradation was found to be the pH of the solution.

The pH of the liquid medium containing the chloral hydrate is a very pertinent characteristic of the hydrolytic degradation it can undergo. In summary, the hydrolysis rate of degradation is controlled by the ambient pH and storage temperature. The degradation of the chloral hydrate API in the aqueous oral solution cannot be chemically stopped (unless it is in a fully non-aqueous matrix), but it can be controlled by the chemical (pH) and physical (temperature) environment. Therefore, stressing study conditions such as thermal conditions, which enhance this degradation mechanism were used as accelerated stability conditions to conduct studies and determine the pH at which the solution would be stable and provide the desired shelf life of the chloral hydrate solution. The pH that provides optimum stability of the oral solution of the present invention was determined through various experiments. The term "pH that provides optimum stability" means a pH suitable for oral administration, i.e. not too acidic to impact taste, nor alkaline to cause degradation of the chloral hydrate, the target being a stable solution of chloral hydrate. The term "stable" as used herein refers to an oral chloral hydrate solution with not more than 300 ppm of chloroform and not more than 800 ppm of formic acid at the end of at least 12 months, upon storage of the solution below 25 °C. In preferred embodiments the chloral hydrate solution of the present invention is stable for at least 24 months.

In the oral chloral hydrate solution of the present invention, the chloroform specification is set at "not more than 300 ppm', which relates to the ICH Residual Solvent specification for this Class II solvent. The chloroform compound itself is not a residual solvent as such in this product, but as discussed above, it is a potential degradation product in the finished product, i.e. the oral solution. Similarly, the specification for formic acid, which is also a degradation product of chloral hydrate, is set at "not more than 800 ppm-which is below the ICH Residual Solvent specification of 5000 ppm for this Class III solvent Chloral hydrate API may contain monochloroacetaldehyde (commonly referred to as MCAT or MCAA) as a process impurity. MCAT is mutagenic or carcinogenic in nature. This impurity must be controlled so that the finished dosage form, i.e. the oral solution, has levels of MCAT that are within acceptable limits. Further, the pharmaceutically acceptable excipients used in the formulation of the oral solution should not cause increase of MCAT upon storage. The MCAT may not be present in an amount more than 100 ppm in the oral solution at the end of shelf life.

An ideal shelf life for the chloral hydrate solution would be at least 12 months or more. A stable chloral hydrate oral solution that has not more than 300 ppm of chloroform, not more than 800 ppm of formic acid and not more than 100 ppm of MCAT at the end of at least 24 months from manufacturing, would be commercially viable and desirable. As discussed above, the prior art suggests use of pH over a wide range. While chloral hydrate solutions with pH between 3-5 were reported to have a shelf life of merely 180 days, some others with pH lower than 3 were found to be highly acidic, irritating and with a bad taste. Though the degradation of chloral hydrate to chloroform was known in the art, there was nothing in the prior art that provided a teaching, suggestion or motivation to obtain a stable product, as described herein, with a shelf life of at least 12 months or more, and which would not have issues related to taste.

The present invention provides a stable chloral hydrate oral solution having a pH of about 3.2 to about 4.5. The pH range of about 3.2 to about 4.5 is critical and was surprisingly found by the present applicants to provide a stable solution with a long shelf life of at least 12 months or more, wherein the levels of chloroform and formic acid in the solution are controlled, when stored below 25 °C In a highly preferred embodiment of the present invention the oral chloral hydrate solution has a pH of about 3.2 to about 4.5 and is stable for a period of at least 24 months, when stored below 25 °C.

The pharmaceutically acceptable excipients used in the chloral hydrate solution of the present invention are those that are conventionally used in oral solutions, and are well known to persons of skill in the art of formulating oral dosage forms. So long as the pH of the solution is maintained between about 3.2 to about 4.5 the use of conventional excipients is found to be permissible The applicants of the present invention conducted trial batches with different ratios of the citric acid: sodium citrate buffer, such as 60:40, 70:30 and 82:18 for the 143mg/5m1 strength, wherein the chloral hydrate solution was found to have pH in the range of about 3.2 to about 4.5. These buffered solutions were subjected to stability studies and tested for levels of chloroform and formic acid. The acceptable conditions were that the chloral hydrate solution should have not more than 300 ppm of chloroform and not more than 800 ppm of formic acid at the end of the desired shelf life, i.e. when stored under accelerated storage conditions, the results obtained at the end of the testing period must extrapolate to a shelf-life of at least 24 months. The stability studies were carried out under two conditions -(i) 25°C / 60% relative humidity (RH), and (ii) 30°C / 65% RH, and the products were tested at the end of 3, 6 and 9 months of storage.

Generally, any buffer that maintains the pH of the chloral hydrate solution in the range of about 3.2 to about 4.5 may be used. Thus, a stable solution of chloral hydrate can be achieved by using the appropriate quantity of buffer and buffer components, such that the pH is in the range of about 3.2 to about 4.5. This pH range may be achieved by using a suitable buffering capacity of the buffering components. Examples of buffers that may be used in the oral chloral hydrate solution of the present invention include, but are not limited to, citrate, acetate, phosphate and mixtures thereof Alternatively, the pH may be adjusted to the desired range of about 3.2 to about 4.5 with a suitable amount of a pH adjusting agent such as hydrochloric acid, water-soluble organic acids, and mixtures thereof Examples of pH adjusting agents include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, malic acid, maleic acid, succinic acid, lactic acid, their pharmaceutically acceptable salts and mixtures thereof Typically, 0.1N hydrochloric acid solution may be used.

The oral chloral hydrate solution of the present invention may include one or more of a diluent, suspending agents, sweetener, flavouring agent, antimicrobial agent (preservative). These are typically selected from the excipients conventionally used in the art and known to a person of skill in the art of formulating oral dosage forms.

Typical diluents that may be used include, but are not limited to, water, alcohol, liquid glucose, syrup, sorbitol, glycerol, propylene glycol, polyethylene glycol and mixtures thereof The diluent is typically used in amount ranging from about 5% v/v to about 95% v/v.

The suspending agents that may be used in the oral chloral hydrate solution of the invention may be those known in the art such as methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carbomers, carboxymethyl cellulose, sodium croscarmellose, alginates, acacia gum, tragacanth, guar gum, bean gum, carrageenan, xanthan gum, and the like and mixtures thereof The suspending agents may be used in amounts such that a solution of desired viscosity is obtained. By "desired" is meant a viscosity that allows easy pouring of the solution for administration Sweeteners that may be used in the oral chloral hydrate solution of the present invention may be selected from nutritive sweetening agents, non-nutritive sweetening agents and mixtures thereof The nutritive sweetening agents may be selected from, but are not limited to, agave nectar, brown rice syrup, hydrogenated glucose syrup, date sugar, honey, molasses and blackstrap molasses, sorghum syrup, stevia, maple syrup, birch syrup, yacon syrup, lucuma powder, coconut sugar, erythritol, maltitol, mannitol, sorbitol, xylitol, isomalt crystals, lactitol, maltitol and mixtures thereof. The non-nutritive sweetening agents may be selected from, but are not limited to, acesulfame, advantame, alitame, allulose, aspartame, neotame, saccharin, sodium saccharin, sucralose, acesulfame potassium, tagatose, thaumatin, stevioside and mixtures thereof. The sweetener may be used in an amount ranging from about 0.02% to about 70%. In some embodiments, the oral chloral hydrate solution only contains artificial sweeteners and is sugar free.

A flavouring agent or flavourant can be added to enhance the taste or aroma of the oral chloral hydrate solution of the invention Non-limiting examples of suitable natural flavours, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, mango, grape, grapefruit, guava, hop, lemon, licorice, lime, elderberry, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pomegranate, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, winter green, and the like, as well as combinations thereof Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavour and/or a compounded flavouring agent based on fruit flavours. Presently preferred flavouring agent is essence of passion fruit. The flavouring agent may be used in an amount ranging from about 0.3% to about 5%.

Typical antimicrobial agents or preservatives that may be used in the oral chloral hydrate solution of the present invention include, but are not limited to, benzoic acid, methyl paraben, propyl paraben, butyl paraben, sorbic acid and their pharmaceutically acceptable salts, and mixtures thereof The preservative may be present in an amount ranging from about 0.01% to about 3%.

The oral chloral hydrate solution of the present invention can be prepared by processes conventional in the art and known to those of skill in the art. These have been elaborated in the examples provided below.

The oral solutions of the present invention may be stored in amber glass bottles with screw cap made of polypropylene/HDPE/LDPE, and may be presented in a carton. Each pack may contain a 5 ml oral syringe having a polypropylene body and a HDPE plunger, with intermediate graduations of 0.1 ml, and a syringe adapter made of LDPE.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description of the disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

The features disclosed in the foregoing description or in the following claims, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately or in any combination of such features, be utilised for realising the invention in diverse forms thereof Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination Moreover, the present disclosure also contemplates that in some embodiments of the disclosure, any feature or combination of features set forth herein can be excluded or omitted. While the invention has been described in conjunction with the exemplary embodiments described herein, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth herein are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety for all purposes.

Any section headings used herein are for organisational purposes only and are not to be construed as limiting the subject matter described.

As used herein, "ppmrefers to parts per million by weight.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise" and "include", and variations such as "comprises", "comprising", and "including" will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an", and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent -about," it will be understood that the particular value forms another embodiment. The term 'about" in relation to a numerical value (as used herein when referring to a measurable value such as an amount of a compound or agent of this disclosure, dose, time, temperature, pH and the like) is optional and means for example +/-20%.

Also as used herein, and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or")

EXAMPLES Example I

Ingredient Quantity (mg) Chloral hydrate 500 Glucose, liquid 1655 Glycerol 3525 Sodium benzoate 6.3 Saccharin sodium 6.3 Citric acid 16.3 Sodium citrate 7.0 Essence of passion fruit 18.9 Water QS 5m1 Purified Water and Glycerol were mixed for a minimum of 10 minutes until fully dispersed. Chloral Hydrate, Sodium Benzoate and Sodium Saccharin were then added while mixing continuously for a minimum of 30 minutes until fully dissolved to obtain a bulk solution. Citric acid and Sodium Citrate were dissolved in purified water in a separate container. This solution was added to the bulk solution and mixed for a minimum of 10 minutes until fully dispersed. Liquid Glucose was warmed to 45 °C and added to the above solution and mixed continuously for a minimum of 15 minutes until fully dispersed. Passion Fria Essence was then added and mixed for 30 minutes until fully dispersed. The solution thus obtained was filtered through stainless steel filters and filled in bottles. The final solution has a pH of 4.4.

Example 2

The chloral hydrate solution obtained in Example I was subjected to stability testing at accelerated conditions mentioned in the table below, and the product was tested at 3 months and 6 months. The results of the stability test are included in Table 1 below.

Table 1

Storage condition 3 months/bottle in upright position 6 months/bottle in upright position Amount of chloroform in Amount of formic acid in Amount of chloroform in Amount of formic acid in PPm PPm PPm PPm 25°C/60% RH 52 17 96 NA 30°C/65°0 RH 146 39 270 NA As can be seen in the table above, the chloral hydrate solution of Example 1, which contains citric acid -sodium citrate in a 70:30 ratio, has less than 300 ppm of chloroform at the end of 6 months when stored at the accelerated conditions, indicating that the product would have a shelf life of more than 6 months when stored below 25 °C.

Example 3

Ingredient Quantity (mg) Chloral hydrate 500 Glucose, liquid 1655 Glycerol 3525 Sodium benzoate 6.3 Saccharin sodium 6.3 Citric acid 19.1 Sodium citrate 4.2 Essence of passion fruit 18.9 Water QS 5m1 The chloral hydrate solution was obtained by the process described in Example 1 above, as a 50 liter batch. The oral solution contains citric acid -sodium citrate in an 821 8 ratio, and the solution has a pH of 4.1

Example 4

The chloral hydrate solution obtained in Example 3 was subjected to stability testing at accelerated conditions mentioned in the table below, and the product was tested at 6 months and 9 months. The results of the stability test are included in Table 2 (bottles stored in upright position) and Table 3 (bottles stored in inverted position).

Table 2

Storage condition 6 months/bottle in upright position 9 months/bottle in upright position Amount of chloroform in ppm Amount of formic acid in ppm Amount of chloroform in ppm Amount of formic acid in ppm 25°C/60% RH 46 21 63 30 30°C/65% RH 123 42 160 59

Table 3

Storage condition 6 months/bottle in inverted position 9 months/bottle in inverted position Amount of chloroform in ppm Amount of formic acid in ppm Amount of chloroform in ppm Amount of formic acid in ppm 25°C/60% RH 49 51 67 31 30°C/65% RH 131 43 173 62 As can be seen in Tables 2 and 3 above, the chloral hydrate solution of Example 3, which contains citric acid -sodium citrate in an 82:18 ratio, has less than 300 ppm of chloroform and less than 800 ppm of formic acid at the end of 9 months when stored at the intermediate accelerated conditions, indicating that the product would have a shelf life of at least 24 months when stored below 25 °C.

Example 5

An additional 50 liter batch, similar in composition to Example 3, was executed and the solution thus obtained was subjected to stability testing at accelerated conditions. The results of the testing are included in Table 4 (bottles stored in upright position) and Table 5 (bottles stored in inverted position).

Table 4

Storage condition 6 months/bottle in upright position 9 months/bottle in upright position Amount of chloroform in ppm Amount of formic acid in ppm Amount of chloroform in ppm Amount of formic acid in ppm 25°C/60% RH 45 18 60 30 30°C/65% RH 125 41 167 63

Table 5

Storage condition 6 months/bottle in inverted position 9 months/bottle in inverted position Amount of chloroform in ppm Amount of formic acid in ppm Amount of chloroform in ppm Amount of formic acid in ppm 25°C/60% RI -I 45 18 60 30 30°C/65°/0 RH 129 42 171 62 As can be seen in Tables 4 and 5 above, the chloral hydrate solution has less than 300 ppm of chloroform and less than 800 ppm of formic acid at the end of 9 months when stored at the accelerated conditions, indicating that the product would have a shelf life of at least 24 months when stored below 25 °C.

Example 6

Ingredient Quantity (mg) Chloral hydrate 143.30 Glucose, liquid 1655 Glycerol 3525 Sodium benzoate 6.30 Saccharin sodium 6.30 Citric acid 19.11 Sodium citrate 4.20 Essence of passion fruit 18.90 Water QS 5m1 A chloral hydrate solution of strength 143mg/5m1 was prepared using the above inactive ingredients, using a process similar to that disclosed in Example 1 above The solution above used a citric acid: sodium citrate ratio of 82:18. Similar solutions using citric acid: sodium citrate ratios of 60:40 and 70:30 were also prepared using a similar process. The p1-1 of the solutions was found to be about 3.2 to about 4.5. All solutions were found to be stable when stored at 25°C, 60% relative humidity, over a period of 6 months. The chloroform content in these solutions was found to stay below 300 ppm at the end of 6 months. An extrapolation of the data indicates that the shelf life of the solution was at least 24 months.

Claims

CLAIMS1. A chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/m1 to about 100mg/m1 and one or more pharmaceutically acceptable excipients, wherein the solution has a pH of about 3.2 to about 4.5.
2. The chloral hydrate solution of claim 1 wherein the solution has a. no more than 300 ppm of chloroform, b. no more than 800 ppm of formic acid and c. no more than 100 ppm of monochloroaceta1dehyde, when stored at 25 °C, 60% relative humidity for 9 months.
3. The chloral hydrate solution of either claim 1 or claim 2 wherein the one or more pharmaceutically acceptable excipients include one or more of a buffer, a pH adjusting agent, diluent, suspending agent, sweetener, flavouring agent and antimicrobial agent.
4. The chloral hydrate solution of claim 3 wherein the one or more pharmaceutically acceptable excipients include a buffer, such that the solution is buffered between a pH of about 3.2 and about 4.5.
5. The chloral hydrate solution of claim 3 wherein the one or more pharmaceutically acceptable excipients include a buffer, such that the solution is buffered between a pH of about 3.7 and about 4.5.
6. The chloral hydrate solution of claim 3 wherein the one or more pharmaceutically acceptable excipients include a buffer, such that the solution is buffered between a pH of about 4.1 and about 4.4.
7. The chloral hydrate solution of any one of claims 4 to 6 wherein the buffer is selected from citrate, acetate, phosphate and mixtures thereof 8. The chloral hydrate solution of claim 7 wherein the buffer is a mixture of citric acid and sodium citrate.9. The chloral hydrate solution of claim 8 wherein the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 90:10 by weight.The chloral hydrate solution of claim 8 wherein the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 82:18 by weight.11 The chloral hydrate solution of claim 8 wherein the buffer is a mixture of citric acid and sodium citrate in a ratio of about 70:30 to about 82:18 by weight.12 The chloral hydrate solution of claim 3 wherein the one or more pharmaceutically acceptable excipients include a pH adjusting agent.13 The chloral hydrate solution of claim 12 wherein the pH adjusting agent is selected from hydrochloric acid, a water soluble organic acid and mixtures thereof 14 The chloral hydrate solution of any one of claims 3 to 13 wherein the diluent is selected from water, alcohol, liquid glucose, syrup, sorbitol, glycerol, propylene glycol, polyethylene glycol and mixtures thereof.The chloral hydrate solution of any one of claims 3 to 14 wherein the sweetener is selected from agave nectar, brown rice syrup, hydrogenated glucose syrup, date sugar, honey, molasses, blackstrap molasses, sorghum syrup, stevia, maple syrup, birch syrup, yacon syrup, lucuma powder, coconut sugar, erythritol, maltitol, mannitol, sorbitol, xylitol, isomalt crystals, lactitol, maltitol, acesulfame, advantame, alitame, allulose, aspartame, neotame, saccharin, sodium saccharin, sucralose, acesulfame potassium, tagatose, thaumatin, stevioside and mixtures thereof 16 The chloral hydrate solution of any one of claims 3 to 15 wherein the flavouring agent is selected from almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, mango, grape, grapefruit, guava, hop, lemon, licorice, lime, elderberry, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pomegranate, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, winter green, tutti-frutti, bubblegum and mixtures thereof 17 The chloral hydrate solution of any one of claims 3 to 16 wherein the antimicrobial agent is selected from benzoic acid, methyl paraben, propyl paraben, butyl paraben, sorbic acid and their pharmaceutically acceptable salts, and mixtures thereof 18 The chloral hydrate solution of any one of claims 1 to 17 wherein the solution has no more than 300 ppm of chloroform, no more than 800 ppm of formic acid and no more than 100 ppm of monochloroacetaldehyde for 24 months when stored below 25 °C.19 The chloral hydrate solution of any one of claims 1 to 18 wherein the chloral hydrate is present in an amount of about 500mg/5m1.The chloral hydrate solution of any one of claims 1 to 18 wherein the chloral hydrate is present in an amount of about 143mg/5m1.21 The chloral hydrate solution of any one of claims 1 to 20 for use in a method of treatment of the human or animal body.22 The chloral hydrate solution of any one of claims 1 to 20 for use in the treatment of insomnia.23. The chloral hydrate solution of any one of claims Ito 20 for use in a method of sedating a subject.24 The chloral hydrate solution for use according to any one of claims 21 to 23, wherein the chloral hydrate solution is administered orally.A method of preparing the chloral hydrate solution of any one of claims 1 to 20, comprising mixing the chloral hydrate with the one or more pharmaceutically acceptable excipients in an aqueous solution.