PHARMACEUTICAL LIQUID COMPOSITION, KIT OF PARTS COMPRISING THE PHARMACEUTICAL LIQUID COMPOSITION, AND METHOD FOR PREPARING THE PHARMACEUTICAL LIQUID COMPOSITION

Abstract

A pharmaceutical liquid composition includes a solution of a physiologically acceptable salt of 4-phenylbutyric acid, which in one embodiment is the sodium salt of 4-phenylbutyric acid, in an aqueous medium at a concentration of at least 1.34 mmol/ml. The aqueous medium includes glycerol; a viscosity enhancing agent, where the viscosity enhancing agent includes a cellulose derivate, and water. The pharmaceutical liquid composition further includes a sweetening agent.

Claims

1-35. (canceled)

36. A pharmaceutical liquid composition comprising a solution of a physiologically acceptable salt of 4-phenylbutyric acid, preferably the sodium salt of 4-phenylbutyric acid, in an aqueous medium at a concentration of at least 1.34 mmol/ml; wherein the aqueous medium comprises: a. glycerol, in particular having a volume concentration of at least 1.0 ml/l relative to the total volume of the aqueous medium, preferably in the range 5.0 ml/1 to 20.0 ml/l relative to the total volume of the aqueous medium; b. a viscosity enhancing agent, wherein the viscosity enhancing agent comprises a cellulose derivate; and c. water; and wherein the pharmaceutical liquid composition further comprises a sweetening agent, wherein the sweetening agent comprises a natural sweetening agent and/or an artificial sweetening agent, wherein the natural sweetener is selected from the group consisting of sucrose, dextrose, fructose, sorbitol, xylitol, vanilla, mannitol and mixtures thereof and wherein the artificial sweetener is selected from the group consisting of sodium saccharine, sodium cyclamate, aspartame, lacititol, isomalt, sucralose acesulfame K, neohespiridine, sucralose and mixtures thereof, and wherein the weight ratio between the glycerol and the viscosity enhancing agent is between 200:1 and 10:1.

37. The pharmaceutical liquid composition according to claim 36, wherein the pH of the liquid composition is in the range of 6.0 to 10.0.

38. The pharmaceutical liquid composition according to claim 36, wherein the viscosity enhancing agent has a concentration of at least 0.001 g/ml relative to the total volume of the aqueous medium.

39. The pharmaceutical liquid composition according claim 36, wherein the viscosity of the liquid composition is in the range of 100 mPa.Math.s-1000 mPa.Math.s at 25° C.

40. The pharmaceutical liquid composition according to claim 36, wherein the sweetening agent comprises aspartame and sucrose and wherein the concentration of aspartame relative to the concentration of sucrose is in the range 1:2 to 2:1.

41. The pharmaceutical liquid composition according claim 36, wherein the viscosity enhancing agent comprises a hydroxyethylcellulose having a weight average molecular weight in the range of 200.000-2.000.000 Da.

42. A kit of parts comprising: a pharmaceutical liquid composition according to claim 36; and at least one flavouring liquid concentrate, the flavouring concentrate comprising at least one flavouring agent, preferably a first flavouring agent and a second flavouring agent.

43. The kit of parts according to claim 42, wherein each flavouring agent has a concentration in the range of 5-100 weight-% of the total weight of the flavouring liquid concentrate and the sum of the at least one flavouring agent is in the range of 80-100 weight-% of the total weight of the flavouring liquid concentrate.

44. The kit of parts according to claim 42, wherein the kit comprises a medical dropper for administering drops of the at least one flavouring liquid concentrate.

45. The kit of parts according to claim 42, wherein each of the at least one flavouring agent is selected from the group consisting of a fruit flavour, mint, ginger, caramel, liquorice, peppermint and eucalyptol flavours and mixtures thereof.

46. A method for preparing a pharmaceutical liquid composition comprising an aqueous medium wherein the aqueous medium comprises glycerol and water, wherein the pharmaceutical liquid composition is according to claim 36, the method comprising the steps of: a. providing glycerol; b. adding the viscosity enhancing agent to the glycerol, while stirring, preferably continuously, the glycerol to form a mixture of viscosity enhancing agent and glycerol, wherein the viscosity enhancing agent comprises a cellulose derivate; c. providing a solution of a physiologically acceptable salt of 4-phenylbutyric acid in water; d. adding the solution of the physiologically acceptable salt of 4-phenylbutyric acid to the mixture of viscosity enhancing agent and glycerol, while stirring said mixture to form a solution of the physiologically acceptable salt of 4-phenylbutyric acid in the aqueous medium; e. optionally allowing the aqueous medium to swell, while stirring the aqueous medium; f. optionally adding a sweetening agent to the solution of a physiologically acceptable salt of 4-phenylbutyric acid in water before step d. forming the solution of the physiologically acceptable salt of 4-phenylbutyric acid in the aqueous medium and wherein the physiologically acceptable salt of 4-phenylbutyric acid has a concentration of at least 1.34 mmol/ml in the aqueous medium.

47. The method for preparing the pharmaceutical liquid composition according to claim 46, wherein the amount of viscosity enhancing agent added to the glycerol during step b. is selected such that the concentration of the viscosity enhancing agent in the resulting mixture is in the range of 0.01 g/ml to 0.10 g/ml.

48. The method for preparing the pharmaceutical liquid composition according to claim 46, wherein the viscosity enhancing agent is dispersed in glycerol when adding the solution of the physiologically acceptable salt of 4-phenylbutyric acid to the mixture of viscosity enhancing agent and glycerol.

49. Pharmaceutical liquid formulation according to claim 36 for use as a medicament.

50. The pharmaceutical liquid formulation according to claim 49, wherein the pharmaceutical liquid composition is administered using a nasogastric and/or gastronomy tube.

51. The pharmaceutical liquid formulation according to claim 49, wherein the pharmaceutical liquid solution is administered to a patient in need thereof, the administering comprising: a. adding an amount of the pharmaceutical liquid composition to water to form a mixture, wherein the volume ratio between the pharmaceutical liquid composition and water is in the range of 1:20 to 1:1; and b. orally administering said mixture to the patient.

52. The pharmaceutical liquid formulation according to claim 49, wherein the pharmaceutical liquid composition is used for daily administering to the patient.

53. The pharmaceutical liquid formulation according to claim 52, wherein the amount of the pharmaceutical liquid composition added in step a. to water is in the range 0.5 ml to 20.0 ml.

54. The pharmaceutical liquid formulation according to claim 51, wherein the pharmaceutical liquid composition is part of a kit of parts comprising: the pharmaceutical liquid composition; and at least one flavouring liquid concentrate, the flavouring concentrate comprising at least one flavouring agent, preferably a first flavouring agent and a second flavouring agent; the method further comprising a step before the oral administering step of: c. adding an amount of one or more of said at least one flavouring liquid concentrate to the mixture of step a. or to the water, which is used in step a. to form the mixture.

55. The pharmaceutical liquid formulation according to claim 54, wherein the kit of parts comprises at least two flavouring liquid concentrates and wherein the step of adding one or more flavouring liquid concentrates comprises selecting an amount of drops of a first flavouring liquid concentrate and selecting an amount of drops of a second flavouring liquid concentrate.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0100] The accompanying drawings are used to illustrate presently preferred non-limiting exemplary embodiments of devices of the present invention. The above and other advantages of the features and objects of the invention will become more apparent and the invention will be better understood from the following detailed description when read in conjunction with the accompanying drawings, in which:

[0101] FIG. 1 illustrates schematically a process flow for preparing the pharmaceutical liquid composition of an exemplary embodiment;

[0102] FIG. 2 illustrates schematically individual components of a flavouring pharmaceutical liquid kit.

MEASUREMENT METHODS

Viscosity

[0103] Viscosity measuring low-viscous Newtonian fluids using Haake viscotester type D. Haake complies to ISO 2555. Measuring temperature is 20° C., Haake standard spindles are applied (type L1 to L4). Rotational speed: between 0.1 rpm and 200 rpm, measuring viscosity range: between 15 mPas-2.000.000 mPas.

Microbiological Stability

[0104] According to Assay and Stability methods described in US Pharmacopeia-National Formulary (USP/NF), the European Pharmacopoeia (EP).

Constitution/Concentration Stability

[0105] According to Assay and Stability methods described in US Pharmacopeia-National Formulary (USP/NF), the European Pharmacopoeia (EP).

Formulation Example

Pharmaceutical Liquid Compositions

[0106] Pharmaceutical liquid composition A is a Sodium Phenylbutyrate 350 mg/mL taste masked aqueous solution composition per liter:

TABLE-US-00001 Quantity A Ingredient (gram) 1 Sodium Phenylbutyrate 350 2 Purified water 648.15 3 Aspartame 2 4 Sucralose 2 5 Glycerol 100% 100 6 Natrosol 250 HX Pharm* 4 1 liter= 1106.15 *Hydroxyethylcellulose

[0107] The Sodium Phenylbutyrate may be abbreviated as SPB in the description. Natrosol 250 HX Pharm has a weight average Mw of 1.000.000 Da.

[0108] Natrosol 250 HX Pharm is a hydroxyethylcellulose. Said hydroxyethylcellulose may be dispersed in glycerol and may then dissolve readily in cold or hot water to form clear and smooth solutions. Furthermore, it does not precipitate even when heated.

[0109] Several alternative liquid compositions B-D were made having the same composition, however having the following concentrations of Sodium Phenylbutyrate: 200 mg/mL (B), 160 mg/mL (C) and 120 mg/mL (D).

[0110] It has been found that the cellulose derivate is suitable for thickening the pharmaceutical liquid composition and controlling the viscosity of the pharmaceutical liquid composition, while not disturbing a solubility of the physiologically acceptable salt of 4-phenylbutyric acid. In addition, the solubility and thickening effect of the cellulose derivate remains substantially unaffected by a pH of the pharmaceutical liquid composition, which may be in alkaline pH regions (i.e. >7.0) for higher concentrations of the physiologically acceptable salt of 4-phenylbutyric acid.

[0111] Furthermore, it has been found that Xanthan gum is not suitable for thickening the pharmaceutical liquid composition and controlling the viscosity of the pharmaceutical liquid composition. Xanthan gum has been found to be insufficiently soluble in water. As such, it is expected that Xanthan gum may disturb a solubility of the physiologically acceptable salt of 4-phenylbutyric acid.

[0112] Furthermore, it has been found that carbomers (carboxyvinyl polymers) are not not suitable for thickening the pharmaceutical liquid composition and controlling the viscosity of the pharmaceutical liquid composition. The carbomers are not compatible to the pharmaceutical liquid composition having a physiologically acceptable salt of 4-phenylbutyric acid of at least 1.34 mmol/ml, such as at least 250 mg/ml for sodium 4-phenylbutyric acid.

[0113] A concentration of the sodium salt of 4-phenylbutyric acid in the aqueous medium may be determined based on the dry weight of sodium 4-phenylbutyric acid in grams (or milligrams [mg]) with respect to a volume of the aqueous medium in liters (or milliliter [ml]).

[0114] A concentration of a physiologically acceptable salt of 4-phenylbutyric acid in the Pharmaceutical liquid composition may be determined or assessed by measuring the concentration of 4-phenylbutyric acid in mmol/ml using High-performance liquid chromatography (HPLC) technique. HPLC techniques to determine the concentration of 4-phenylbutyric acid in an aqueous medium are generally known. The HPLC technique may be optimized to separate the 4-phenylbutyric acid from the other components of the pharmaceutical liquid composition depending on the composition of the pharmaceutical liquid composition. Additionally, it may be checked by known techniques that substantially an equal amount of sodium (expressed in mmol/ml) as the 4-phenylbutyric acid (expressed in mmol/ml) is present in the pharmaceutical liquid composition.

Kit Compositions

[0115] The kit is comprised of a pharmaceutical liquid composition according to the invention, such as the Pharmaceutical liquid composition A described above, and one or more flavouring liquid concentrate compositions.

[0116] FIG. 2 shows a kit 100 including a pharmaceutical liquid composition 110 and three flavouring liquid concentrate compositions 120, 130, 140. The pharmaceutical liquid composition 110 is contained in a bottle, such as a glass bottle. The bottle may contain a volume in the range of 50 ml, 100 ml or 200 ml of the pharmaceutical liquid composition. Optionally a medical syringe 210 may be provided to administer the pharmaceutical liquid composition 110 in an amount of 0.5 ml-20.0 ml. The medical syringe 210 can be used together with an insert 220, which can be inserted in the bottle 110, to accurately

[0117] Preferably, to eliminate common errors in dosing pharmaceutical liquid compositions a specially dosing device is selected, i.e. an oral syringe fitted with a volume dosing (mL) scale and/or a corresponding active substance scale (mg).

[0118] Example: a newborn approx. 3.4 kg in body weight theoretically requires 4.8 mL undiluted of the pharmaceutical composition/day −measured with an accuracy in the range of +/−5% (at a low volume around 0.5-2.5 ml) or even better (at volumes larger than 2.5 ml). The same oral syringe is fitted with an active substance corresponding weight scale (mg). In this case measuring 4.8 mL corresponds with a 1.7 g active substance dose. Where the corresponding active substance weight (mg) correlates with the active substance concentration of the pharmaceutical liquid composition.

[0119] Each of the three flavouring liquid concentrate compositions 120, 130, 140 is contained in a smaller bottle, such as a glass bottle. The bottle may contain 3 ml-10 ml of the flavouring liquid concentrate composition. Each bottle of the flavouring liquid concentrate has a cap 144 and may further contain a medical dropper, such as a dropper insert 142, to administer drops of the flavouring liquid concentrate.

[0120] In alternative embodiments, the kit 100 may have one flavouring liquid concentrate composition contained in a bottle, may have two flavouring liquid concentrate compositions individually packed in a bottle, or any other suitable number of flavouring liquid concentrate composition individually packed in a bottle.

Flavouring Liquid Concentrate Compositions

[0121] Batch formula; —Mango-Orange drops—inactive ingredient—topping flavor composition A

TABLE-US-00002 Quantity (g) Quantity p/100 mL batch Ingredient (p/gram) (100 mL = ±92 g) 1 Mango CRA 1221L 0.495 45.54 2 Orange CRA 1028L 0.388 35.81 3 Peppermint CRA 1418L 0.117 10.79 1.000 92.33

[0122] Batch formula; — Blackcurrant drops—inactive ingredient—topping flavor composition B

TABLE-US-00003 Quantity (g) Quantity p/100 mL batch Ingredient (p/gram) (100 mL = ±96 g) 1 Blackcurrant CRA 1198L 0.885 84.96 2 Peppermint CRA 1418L 0.115 11.04 1.000 96.00

[0123] Batch formula; — Lemon—Mint drops—inactive ingredient—topping flavor composition C

TABLE-US-00004 Quantity (g) Quantity p/100 mL batch Ingredient (p/gram) (100 mL = ±87 g) 1 Lemon CRA 1190L 0.794 69.44 2 Peppermint CRA 1418L 0.206 18.06 1.000 87.50

Methods for Preparing the Compositions

Pharmaceutical Liquid Composition

[0124] Equipment: stainless steel tanks (2), propeller stirrer (preferably portable), bottles filling line

Description of the Manufacturing Process:

[0125] 1. Dispense raw materials [0126] 2. Fill a suitable primary stainless steel tank with the Glycerol 100% [0127] 3. Gradually add and disperse the Natrosol 250 HX Pharm in the Glycerol, whilst stirring continuously [0128] 4. Verify visually if the Natrosol 250 HX Pharm is homogeneously dispersed [0129] 5. Fill a suitable secondary stainless steel tank with the available purified water [0130] 6. Gradually (step-by-step) add and dissolve the Sodium Phenylbutyrate in the Purified water, whilst stirring continuously [0131] 7. Verify visually if the Sodium Phenylbutyrate is completely dissolved [0132] 8. Gradually add and dissolve the Aspartame and Sucralose whilst stirring continuously [0133] 9. Verify visually if the Aspartame and Sucralose is completely dissolved [0134] 10. Gradually add the Sodium Phenylbutyrate/Aspartame/Sucralose solution to the primary tank with the Glycerol 100%/Natrosol 250 HX Pharm dispersion, whilst stirring continuously [0135] 11. Allow the complete solution to swell for several minutes (Example: 10-15 min at 2 liter scale), whilst stirring continuously [0136] 12. Verify visually if the final solution is homogeneous and clear [0137] 13. Sample the bulk solution for in-process analysis prior to filling, verifying assay Sodium Phenylbutyrate [0138] 14. Fill the bulk solution into selected bottles [0139] 15. Sample filled bottles for final product QC release analysis according to product specifications [0140] 16. Label the bottles

[0141] A workflow for a process of preparing the pharmaceutical liquid composition according to an embodiment is shown in FIG. 1.

[0142] In step S10 a first tank is provided with glycerol. In step S20 a viscosity enhancing agent, preferably a cellulose derivate, in an example Natrosol 250 HX, is gradually added and dispersed in the glycerol, while stirring the glycerol continuously.

[0143] In step S30 it is verified, such as visually, that the viscosity enhancing agent is homogeneously dispersed in the glycerol. After step S30 a mixture A of viscosity enhancing agent and glycerol is provided, wherein the viscosity enhancing agent is dispersed in glycerol.

[0144] In step S110 a second tank is provided with purified water. In step S120 a physiologically acceptable salt of 4-phenylbutyric acid, such as sodium phenylbutyrate, is gradually added and dissolved in the water, while stirring the solution continuously.

[0145] In step S130 it is verified, such as visually, that the salt of 4-phenylbutyric acid is dissolved in water.

[0146] In step S140 at least one sweetening agent, such as aspartame and/or sucrose, is gradually added and dissolved, while stirring the solution continuously. In step S150 it is verified, such as visually, that the sweetening agent or sweetening agents is/are dissolved in water. After step S150 a solution B of salt of 4-phenylbutyric acid and sweetening agent in water is provided.

[0147] In step S210 the solution B is gradually added to the mixture A of viscosity enhancing agent and glycerol, while stirring the mixture continuously. After adding the solution B, in step S220 the aqueous medium of the mixture is allowed to swell for minutes, while stirring the aqueous medium continuously. In step S230 it is verified, such as visually, that the final solution C is homogeneous and clear. The viscosity enhancing agent is completely dissolved in the aqueous medium.

[0148] In an example, the solution B has a concentration of sodium phenylbutyrate such that the concentration of sodium phenylbutyrate in the solution C is at least 250 mg/ml.

Flavouring Liquid Concentrate Compositions

Manufacturing Method;

[0149] Equipment: Erlenmeyer flask with cover, portable lab-scale propeller stirrer, bottles filling equipment. Note: possibility to flush Erlenmeyer flask and bottles with Nitrogen (prior/during mixing/filling)

Description of the Manufacturing Process:

[0150] 1. Dispense raw materials [0151] 2. Flush the Erlenmeyer flask with nitrogen prior to adding ingredients and close the flask [0152] 3. Open the flask briefly and add the liquid flavoring agents, flush the tank again with nitrogen [0153] 4. Close the flask directly after and mix ingredients for approx. 10 minutes [0154] 5. Verify visually if the blend is homogeneous, sample the mixture for release [0155] 6. Flush the flask again with nitrogen and close the flask [0156] 7. Fill the bulk mixture into selected bottles, whilst flushing with nitrogen [0157] 8. Sample filled bottles for final product QC release analysis according to product specifications [0158] 9. Label the bottle

Properties

Solution Stability

[0159] Testing of solubility of Sodium Phenylbutyrate (SPB) in purified water at concentrations of 500 mg/ml, 450 mg/ml, 400 mg/ml and 350 mg/ml demonstrated that the latter concentration was the most efficient concentration for implementation in a conventional manufacturing process. SPB concentrations higher than 350 mg/ml created significant lumping of the SPB during the dissolving process.

[0160] For the 500 mg/ml concentration it was even required to pre-heat (40° C.) the purified water to dissolve the SPB completely.

Test Procedure

[0161] 500 mg/ml (required pre-heating of water), 450 mg/ml, 400 mg/ml and 350 mg/ml solutions were packed in clear glass bottles and stored for 2 weeks at 25° C., 40° C. and 5° C. Only the SPB 500 mg/ml showed crystallization after 1 week at 40° C.

[0162] Considering the technical difficulties associated with dissolving SPB at concentrations higher than 350 mg/ml, it was concluded that the risk of creating a near saturated SPB solution above the 350 mg/ml concentration was present.

[0163] This selection is particularly relevant because the previous represents a baseline formulation to which a number of additional (taste masking) supportive inactive ingredients required to completely dissolve in the available aqueous component of the formulation.

Comparison Experiments

[0164] Two potentially suitable preservative systems, known to be effective in alkaline pH regions, were identified and analyzed for compatibility in prototype sodium salt of 4-phenylbutyric acid 350 mg/mL aqueous solution formulation A, i.e. chlorhexidine diacetate (0.5% g/v) and Domiphen bromide (0.5% g/v).

[0165] The prototype solutions contained 4-phenylbutyric acid 350 mg/mL in combination with the chlorhexidine diacetate (0.5% g/v) or Domiphen bromide (0.5% g/v), respectively, dissolved in water.

[0166] Prototype solution samples stored at room temperature were analyzed for sodium salt of 4-phenylbutyric acid assay at time points T=0, T=24 hours and T=48 hours and results showed a decrease in assay over 48 hours, these preservatives were rejected because of suspected interactions between the active compound and selected preservatives and for regulatory reasons.

Preservative Effect of Pharmaceutical Liquid Composition

[0167] Conducted Preservative Efficacy Tests (PET) and Bioburden tests with formulations, containing SPB 350 mg/mL (formulation A), 200 mg/mL (formulation B), 160 mg/mL (formulation C) and 120 mg/mL (formulation D) unexpectedly confirmed self-preserving properties of SPB in aqueous solutions for an the formulations A-D. Unexpected results because in theory the alkaline pH of the solution by itself would not be sufficient. Challenge tests have been carried out with all formulations A-D (which additionally contained lemon mint and mango orange flavour components). All formulations A-D passed the Challenge tests.

[0168] Supportive bacteriostatic, fungicidal properties of glycerol were considered to substantiate self-preserving properties of SPB 350 mg/mL, 200 mg/mL, 160 mg/mL and 120 mg/mL in aqueous solutions.

Tube Feeding Stability

[0169] A 6 hour test has been performed wherein a SPB oplossing (350 mg/ml) was circulated at room temperature by a Watson-Marlow 505-S pump, tube diameter 0.2 mm, rpm 50. The pump settings correspond to an almost dropwise output. The speed was controlled to be low to simulate a worst case situation to signal blocking of the tube and/or crystallization of the SPB solution in the tube.

[0170] Blockage of the tube and crystallization of the SPB solution in the tube did not occur during the 6 hours test procedure.

[0171] An enteral tube may be composed of PUR or silicone, but may also be composed of latex or PVC.

Viscosity

[0172] The measurement gave the following results:
Dynamic viscosity of water is 1.00 mPa-s at 20° C.
Dynamic viscosity of glycerol is 1.31 mPa-s at 20° C.
Dynamic viscosity of glycerol-water mixture (at 10% w/v) is 1.36 mPa-s at 20° C.
Dynamic viscosity of Pharmaceutical liquid compositions A is about 250 mPa-s at 20° C.

Flavouring Liquid Concentrate Drops

[0173] The Flavouring liquid concentrates may be dosed in drops by a medical dropper in drop volumes corresponding to 20-40 drops per mL. The drops have a weight in the range of 15 mg to 50 mg per drop.

[0174] It should be appreciated by those skilled in the art that any block diagrams herein represent conceptual views of illustrative units or modules embodying the principles of the invention.

[0175] Whilst the principles of the invention have been set out above in connection with specific embodiments, it is to be understood that this description is merely made by way of example and not as a limitation of the scope of protection which is determined by the appended claims.