Pharmaceutical formulations

Abstract

A pharmaceutical formulation comprising: a Biopharmaceutics Classification System (BCS) Class I active pharmaceutical ingredient (API), or a salt or solution thereof; an agar primary gelling agent; an

Description

[0001] This invention relates to pharmaceutical formulations and more particularly to one for an Active Pharmaceutical Ingredient (API) which is recognised under the Biopharmaceutics Classification System (BCS) as a Class I drug. BACKGROUND

[0002] APIs can be difficult to formulate as their properties differ from API to API. Two of the parameters that challenge a formulation chemist are an APIs solubility and its permeability. Accordingly, APIs are broadly defined as those falling into one of four classification types based on these two parameters. These four types are illustrated in Fig 1.

[0003] Class I APIs have high permeability and high solubility. a. An Example is Metoprolol. b. Class I compounds are well absorbed, and their absorption rate is usually higher than excretion.

[0004] Class II APIs have high permeability and low solubility. a. Examples include Ibuprofen and Naproxen. b. The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.

[0005] Class III API’s have low permeability and high solubility. a. An example is Cimetidine. b. The absorption is limited by the permeation rate, but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied.

[0006] Class IV APIs have low permeability and low solubility. a. An example is Bifonazole. b. These compounds have a poor bioavailability. Usually, they are not well absorbed over the intestinal mucosa and a high variability is expected.

[0007] The APIs are classified in BCS on the basis of solubility, permeability, and also dissolution.

[0008] Solubility class boundaries are based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water.

[0009] Permeability class boundaries are based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non-human systems capable of predicting drug absorption in humans can be used (such as in-vitro culture methods). A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose.

[0010] Dissolution class boundaries include an immediate release product, namely one which is rapidly dissolving, i.e. when no less than 85% of the labelled amount of the drug substance dissolves within 15 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM in a volume of 900 ml or less in the following media: 0.1 M HCI or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

[0011] Most oral formulations take the form of filled capsules or tablets. There is therefore a need to provide alternative dosage forms of many drugs, which dosage forms can be more readily taken by certain patient groups e.g. children, and the elderly.

[0012] Having a “base” formulation which is suitable for a number of different APIs would be advantageous in that it lowers regulatory hurdles and reduce costs in bringing “equivalents” to market.

[0013] Of course, other formulation types are known, and Applicant has developed several drinkable gel-based formulations in areas such as glucose tolerance testing and for delivering nutraceuticals - see respectively: WO2017 / 075672, WO2019215641, WO2024028788 and WO2024134616.

[0014] However, there remains a need to develop pharmaceutical formulations which are easier to swallow or have other benefits e.g. improved shelf life, bioavailability, taste and / or texture.

[0015] In this regard Applicant has also developed a “base formulation” for BCS class II drugs - application number PCT / IB2024 / 054921, but it remains desirable to be able to formulate other BCS class drugs using a common approach rather than having many bespoke formulations.

[0016] It is an object of the present invention to provide alternative pharmaceutical formulations for BCS Class I drugs, as exemplified by, for example, (1) Cetirizine, (2) Doxycycline, (3) Levetiracetam, (4) Bupropion, (5) Venlafaxine and (6) Paracetamol.

[0017] Cetirizine is a second generation anti-histamine, see https: / / en.wikipedia.org / wiki / Cetirizine.

[0018] Branded versions include Allacan, Piriteze, and Zyrtec.

[0019] Doxycycline is a broad-spectrum antibiotic of the tetracycline class used in the treatment of infections caused by bacteria and certain parasites, see https: / / en.wikipedia.orq / wiki / DoxycycHne.

[0020] Branded forms include Doryx, and Vibramycin.

[0021] Levetiracetam is a medication used to treat epilepsy, see https: / / en.wikipedia.org / wiki / Levetiracetam.

[0022] Branded forms include Keppra, Elepsia, and Spritam.

[0023] Bupropion, formerly called amfebutamone, is an atypical antidepressant primarily used to treat major depressive disorder, seasonal affective disorder and to support smoking cessation, see https: / / en.wikipedia.org / wiki / Bupropion.

[0024] Branded forms include Wellbutrin and Zyban.

[0025] Venlafaxine is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, see hftpsV / emwjkipedja^

[0026] Branded forms include Effexor, EfexorXR, and Venbysi XR

[0027] Paracetamol (acetaminophen) is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain, see https: / / en.wikipedia.org / wiki / Paracetamol.

[0028] Branded forms include Tylenol and Panadol.

[0029] From a regulatory perspective it is possible to obtain registration for a new dosage form using an abridged process such as that provided by the FDA using 505(B)(2) regulatory pathways. See for example: https: / / www.fda.gov / media / 156350 / download incorporated by reference. BRIEF SUMMARY OF THE DISCLOSURE

[0030] In accordance with the present inventions there is provided a pharmaceutical formulation comprising: i) a Biopharmaceutics Classification System (BCS) class I Active Pharmaceutical Ingredient (API), or a salt or solution thereof, ii) a primary gelling agent which is agar; iii) a secondary gelling agent which is an alginate; iv) at least one cation donator, v) a preservative, and vi) water.

[0031] Preferably the formulation further comprises one or more of: vii) a pH modifier, and viii) a solubiliser.

[0032] Non-limiting examples of formulations comprising a BCS class I API include formulations in which the API is (by LISAN naming) Cetirizine, Doxycycline, Levetiracetam, Bupropion, Venlafaxine, Paracetamol, or a salt or solution thereof.

[0033] United States Adopted Name (USAN) is a non-proprietary name for a pharmaceutical drug that is assigned by the USAN Council. The same drug may appear under different brand names.

[0034] The terms “primary”, and “secondary” are used to denote the relative proportion (by weight percent) of the respective gelling agents such that the primary gelling agent (agar) is present in the greatest amount and the secondary gelling (alginate) is present in a lesser amount.

[0035] The alternative gel formulations of the invention comprise agar (an elastic as opposed to plastic gel) as the primary gelling agent. On sucking the gel shears releasing water making the delivery system particularly attractive as a delivery means for children and the elderly who find swallowing tablets difficult.

[0036] Agar is outstanding among hydrocolloids. Agar-agar gels can be formed in very dilute solutions, containing as little as 0.5% to 1.0% of agar-agar. These gels are rigid, brittle, have well defined shapes, as well as sharp melting and gelling points. Moreover, they clearly demonstrate the interesting phenomenon of syneresis (spontaneous extrusion of water through the surface of the gel), and hysteresis (temperature interval between melting and gelling temperatures). Gelling occurs at temperatures far below the gel melting temperature. A 1.5% solution of agar-agar forms a gel on cooling to about 32° to 45° C that does not melt below 85° C. This hysteresis interval is a novel property of agar-agar that finds many uses in food applications. The gel strength of the agar-agar is influenced by concentration, time, pH, and sugar content. The pH noticeably affects the strength of the agar gel; as the pH decreases, the gel strength weakens. Sugar content also has a considerable effect over agar gel. Increasing levels of sugar make gels with harder but a less cohesive texture.

[0037] However, to accommodate different class I APIs it proved necessary to incorporate a secondary gelling agent.

[0038] The secondary gelling agent is an alginate. The alginates include: • Sodium alginate (NaCsHrOe), • Potassium alginate (KCsHyOe), and • Calcium alginate (CaCizHuOiz).

[0039] Following extensive studies Applicant determined not only were two specific gelling agents required, but it was necessary to control their relative amounts.

[0040] The two gelling agents are optimally used in the relative proportions (by weight) of about: Agar: Alginate of from 1.6:1 to 5.6:1 more preferably, 2.4:1 to 5.2:1.

[0041] Preferably the agar is present in an amount, by weight %, of from 0.30 to 1.40 and the alginate is present in an amount, by weight %, of from 0.05 to 0.40.

[0042] More preferably the agar is present in an amount, by weight %, of from 0.33 to 1.08 and the alginate is present in an amount, by weight %, of from 0.10 to 0.32.

[0043] The preferred agar is agar-agar and the preferred alginate is sodium alginate.

[0044] To facilitate gelling the cation donator is a divalent cation which facilitates cross linking of the alginate.

[0045] Preferably the iv) at least one divalent cation is calcium or magnesium, offered as a salt.

[0046] In a preferred embodiment the iv) cation donator is magnesium chloride.

[0047] The ratio of alginate (present and measured as the weight of the salt) to the divalent cation (present and measured as the weight of the salt) is from 3:1 to 7:1.

[0048] The amount, by weight %, of the divalent cation (measured as the weight of the salt) is from 0.01 to 0.07.

[0049] Preferably the v) at least one preservative is selected from lactic acid, potassium sorbate, sorbic acid and sodium benzoate.

[0050] In a preferred embodiment the formulation comprising a BCS class I API has as v) the at least one preservative, potassium sorbate.

[0051] Where present the vi) at least one pH modifier is an acidifying agent, alkalizing agent (base) or buffering agent depending on the API. Exemplary modifiers include acetic acid, citric acid, hydrochloric acid, malic acid, phosphoric acid and sodium hydroxide.

[0052] The pH is in general controlled to be between 4.0 and 7.5

[0053] It varies for the API with the favoured pH for the exemplary APIs being: • Cetirizine pH 4.3 to 5.3, preferably pH 4.8 • Doxycycline pH 4.2 to 5.2, preferably pH 4.7 • Levetiracetam pH 6.4 to 7.4, preferably pH 6.9 • Bupropion pH 4.2 to 5.2, preferably pH 4.7 • Venlafaxine pH 4.3 to 5.3, preferably pH 4.8 and • Paracetamol pH 4.3 to 5.3, preferably pH 4.8

[0054] In a preferred embodiment the formulation comprising a BCS class I API has as the acidifying agent, citric acid or base, sodium hydroxide.

[0055] In some embodiments it is desirable to include a solubilising agent.

[0056] One such solubilising agent is glycerol.

[0057] With respect to the weight percent figures, these are based on the essential components specified in the claims and exclude optional excipients with the exception of a solubiliser as illustrated in the Examples including flavouring which may, for example, be added in amounts of up to 2% by weight.

[0058] The actual amounts vary with the particular API selected.

[0059] In a first embodiment the API is Cetirizine or a salt or solution thereof.

[0060] Preferably the salt is a hydrochloride.

[0061] The Cetirizine formulation comprises ingredients (by weight %) in the range as set out in Table 1a. Table 1a Active / Excipient Min % Max % i) Cetirizine hydrochloride 0.02 0.06 v) Preservative 0.02 0.06 iv) Divalent cation 0.02 0.06 ii) Agar 0.40 0.90 iii) Sodium alginate 0.10 0.30 vi) Water 65.00 to 100.00

[0062] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 1b. Table 1b Active / Excipient Min % Max % i) Cetirizine hydrochloride 0.03 0.05 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.06 ii) Agar 0.47 0.88 iii) Sodium alginate 0.14 0.26 vi) Water 69.30 to 100.00 5

[0063] Most preferably still the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 1c and had a pH of 4.8. Table 1c Active / Excipient Mass (g) Percentage (%) i) Cetirizine hydrochloride 0.01 0.04 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.17 0.67 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 99.01 Total 25.25 100.00

[0064] In a second embodiment the API is Doxycycline or a salt or solution thereof.

[0065] The Doxycycline formulation comprises ingredients (by weight %) in the range as 10 set out in Table 2a. Table 2a Active / Excipient Min % Max % i) Doxycycline 0.20 0.60 v) Preservative 0.02 0.10 iv) Divalent cation 0.02 0.06 ii) Agar 0.45 1.40 iii) Sodium alginate 0.10 0.40 vi) Water 65.00 to 100.00 vii) pH modifier 0.00 0.05

[0066] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 2b. Table 2b Active / Excipient Min % Max % i) Doxycycline 0.28 0.51 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.05 ii) Agar 0.55 1.02 iii) Sodium alginate 0.14 0.26 vi) Water 68.97 to 100.00 vii) Sodium hydroxide 0.01 0.03 5

[0067] Most preferably still the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 2c and had a pH of 4.7. Table 2c Active / Excipient Mass (g) Percentage (%) i) Doxycycline 0.10 0.39 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.20 0.79 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 98.52 vii) Sodium hydroxide 0.01 0.02 Total 25.38 100.00

[0068] In a third embodiment the API is Levetiracetam or a salt or solution thereof.

[0069] The Levetiracetam formulation comprises ingredients (by weight %) in the range as 10 set out in Table 3a. Table 3a Active / Excipient Min % Max % i) Levetiracetam 0.60 1.30 v) Preservative 0.02 0.06 iv) Divalent Cation 0.02 0.06 ii) Agar 0.46 0.90 iii) Sodium alginate 0.10 0.30 vi) Water 65.00 to 100.00

[0070] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 3b. Table 3b Active / Excipient Min % Max % i) Levetiracetam 0.69 1.28 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.05 ii) Agar 0.47 0.87 iii) Sodium alginate 0.14 0.26 vi) Water 68.65 to 100.00 5

[0071] Most preferably still the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 3c and had a pH of 6.9. Table 3c Active / Excipient Mass (g) Percentage (%) i) Levetiracetam 0.25 0.98 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.17 0.67 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 98.08 Total 25.49 100.00

[0072] In a fourth embodiment the API is Bupropion or a salt or solution thereof.

[0073] The Bupropion formulation comprises ingredients (by weight %) in the range as set 10 out in Table 4a. Table 4a Active / Excipient Min % Max % i) Bupropion 0.40 0.80 v) Preservative 0.02 0.06 ii) Agar 0.40 1.10 iii) Sodium alginate 0.10 0.40 iv) Divalent cation 0.02 0.07 vii) pH modifier 0.00 0.02 vi) Water 65.00 to 100.00

[0074] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 4b. Table 4b Active / Excipient Min % Max% i) Bupropion 0.41 0.77 v) Potassium sorbate 0.03 0.05 ii) Agar 0.58 1.08 iii) Sodium alginate 0.17 0.32 iv) Magnesium chloride 0.03 0.06 vii) Citric acid 0.01 0.01 vi) Water 68.77 to 100.00

[0075] Most preferably still the formulation comprises ingredients (by weight (g) or weight 5 %) as set out in Table 4c and had a pH of 4.7. Table 4c Active / Excipient Mass (g) Percentage (%) i) Bupropion 0.15 0.59 v) Potassium sorbate 0.01 0.04 ii) Agar 0.21 0.83 iii) Sodium alginate 0.06 0.24 iv) Magnesium chloride 0.01 0.04 vii) Citric acid 0.00 0.01 vi) Water 25.00 98.25 Total 25.45 100.00

[0076] In a fifth embodiment the API is Venlafaxine or a salt or solution thereof.

[0077] The Venlafaxine formulation comprises ingredients (by weight %) in the range as set out in Table 5a. Table 5a Active / Excipient Min % Max % i) Venlafaxine 0.20 0.40 v) Preservative 0.02 0.06 ii) Agar 0.40 1.10 iii) Sodium alginate 0.10 0.40 iv) Divalent Cation 0.02 0.07 vi) pH modifier 0.00 0.03 vii) Water 65.00 to 100.00

[0078] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 5b. Table 5b Active / Excipient Min % Max % i) Venlafaxine 0.21 0.38 v) Potassium sorbate 0.03 0.05 ii) Agar 0.58 1.08 iii) Sodium alginate 0.17 0.32 iv) Magnesium chloride 0.03 0.06 vi) Citric acid 0.01 0.02 vii) Water 68.97 to 100.00

[0079] Most preferably still the formulation comprises ingredients (by weight (g) or weight 5 %) as set out in Table 5c and had a pH of 4.8. Table 5c Active / Excipient Mass (g) Percentage (%) i) Venlafaxine 0.08 0.30 v) Potassium sorbate 0.01 0.04 ii) Agar 0.21 0.83 iii) Sodium alginate 0.06 0.24 iv) Magnesium chloride 0.01 0.04 vi) Citric acid 0.00 0.01 vii) Water 25.00 98.53 Total 25.37 100.00

[0080] In a sixth embodiment the API is Paracetamol or a salt or solution thereof.

[0081] The Paracetamol formulation comprises ingredients (by weight %) in the range as set out in Table 6a. Table 6a Active / Excipient Min % Max% i) Paracetamol 0.90 1.80 v) Preservative 0.01 0.05 iv) Divalent Cation 0.01 0.05 ii) Agar 0.30 0.70 iii) Sodium alginate 0.05 0.20 vii) Water 45.00 to 100.00 viii) Solubiliser 0.00 40.00 vi) pH modifier 0.00 0.20

[0082] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 6b. Table 6b Active / Excipient Min % Max% i) Paracetamol 0.96 1.78 v) Potassium sorbate 0.02 0.04 iv) Magnesium chloride 0.02 0.04 ii) Agar 0.33 0.60 iii) Sodium alginate 0.10 0.18 vii) Water 47.86 to 100.00 viii) Glycerol 20.71 38.47 vi) Citric acid 0.01 0.01

[0083] Most preferably still the formulation comprises ingredients (by weight (g) or weight 5 %) as set out in Table 6c and had a pH of 4.8. Table 6c Active / Excipient Mass (g) Percentage (%) i) Paracetamol 0.50 1.37 v) Potassium sorbate 0.01 0.03 iv) Magnesium chloride 0.01 0.03 ii) Agar 0.17 0.46 iii) Sodium alginate 0.05 0.14 vii) Water 25.00 68.37 viii) Glycerol 10.82 29.59 vi) Citric acid 0.00 0.01 Total 36.56 100.00

[0084] The invention is further described, by way of example only, with reference to the drawing, Examples and detailed description given below. 10 BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Embodiments of the invention are further described hereinafter with reference to the accompanying drawing, in which: Fig 1 is a diagram illustrating the Biopharmaceutics Classification System (BCS). DETAILED DESCRIPTION

[0086] In developing a formulation for BCS class I API’s, Applicant undertook a series of experiments and overcame a number of technical challenges.

[0087] For ease of following, set out below are a series of Examples, for exemplary class I drugs, followed by some comparative Examples which highlight some of the technical challenges overcome.

[0088] Each of the Examples was prepared using the methodology set out below: Method

[0089] Add the API (e.g. Cetirizine, Doxycycline, Levetiracetam, Bupropion, Venlafaxine or Paracetamol), magnesium chloride and potassium sorbate to a beaker. Add glycerol (where applicable) and water and mix until dissolved. Measure the pH of the solution and pH adjust using citric acid or sodium hydroxide, where required. Using a stirring hot plate, heat the solution to 95°C to 100°C. Once the temperature has reached 95°C or above, slowly add the gelling agents, agar and sodium alginate, and mix until completely dissolved. Hot fill the gel into the pouch and cap immediately. Let cool to room temperature. Pouches may require air to inflate the pouch prior to filling. EXAMPLE 1

[0090] The drug Cetirizine was formulated, and the gelling agents were found to provide a satisfactory product when the ingredients were present in amounts (weight %) as illustrated in Table 1a below: Table 1a Active / Excipient Min % Max % i) Cetirizine hydrochloride 0.02 0.06 v) Preservative 0.02 0.06 iv) Divalent cation 0.02 0.06 ii) Agar 0.40 0.90 iii) Sodium alginate 0.10 0.30 | vi) Water|65.00 |to 100.00 |

[0091] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 1b below: Table 1b Active / Excipient Min % Max % i) Cetirizine hydrochloride 0.03 0.05 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.06 ii) Agar 0.47 0.88 iii) Sodium alginate 0.14 0.26 vi) Water 69.30 to 100.00 5

[0092] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 1c below and had a pH of 4.8: Table 1c Active / Excipient Mass (g) Percentage (%) i) Cetirizine hydrochloride 0.01 0.04 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.17 0.67 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 99.01 Total 25.25 100.00 EXAMPLE 2

[0093] The drug Doxycycline was formulated, and the gelling agents were found to provide 10 a satisfactory product when the ingredients were present in amounts (weight %) as illustrated in Table 2a below: Table 2a Active / Excipient Min % Max % i) Doxycycline 0.20 0.60 v) Preservative 0.02 0.10 iv) Divalent cation 0.02 0.06 ii) Agar 0.45 1.40 iii) Sodium alginate 0.10 0.40 vi) Water 65.00 to 100.00 | vii) pH modifier|0.00 |0.05 |

[0094] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 2b below: Table 2b Active / Excipient Min % Max % i) Doxycycline 0.28 0.51 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.05 ii) Agar 0.55 1.02 iii) Sodium alginate 0.14 0.26 vi) Water 68.97 to 100.00 vii) Sodium hydroxide 0.01 0.03 5

[0095] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 2c below and had a pH of 4.7: Table 2c Active / Excipient Mass (g) Percentage (%) i) Doxycycline 0.10 0.39 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.20 0.79 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 98.52 vii) Sodium hydroxide 0.01 0.02 Total 25.38 100.00 EXAMPLE 3

[0096] The drug Levetiracetam was formulated, and the gelling agents were found to 10 provide a satisfactory product when the ingredients were present in amounts (weight %) as illustrated in Table 3a below: Table 3a Active / Excipient Min % Max % i) Levetiracetam 0.60 1.30 v) Preservative 0.02 0.06 iv) Divalent Cation 0.02 0.06 ii) Agar 0.46 0.90 iii) Sodium alginate 0.10 0.30 vi) Water 65.00 to 100.00

[0097] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 3b below: Table 3b Active / Excipient Min % Max % i) Levetiracetam 0.69 1.28 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.05 ii) Agar 0.47 0.87 iii) Sodium alginate 0.14 0.26 vi) Water 68.65 to 100.00 5

[0098] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 3c below and had a pH of 6.9: Table 3c Active / Excipient Mass (g) Percentage (%) i) Levetiracetam 0.25 0.98 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.17 0.67 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 98.08 Total 25.49 100.00 EXAMPLE 4

[0099] The drug Bupropion was formulated, and the gelling agents were found to provide 10 a satisfactory product when the ingredients were present in amounts (weight %) as illustrated in Table 4a below: Table 4a Active / Excipient Min % Max % i) Bupropion 0.40 0.80 v) Preservative 0.02 0.06 ii) Agar 0.40 1.10 iii) Sodium alginate 0.10 0.40 iv) Divalent cation 0.02 0.07 vii) pH modifier 0.00 0.02 vi) Water 65.00 to 100.00

[00100] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 4b below: Table 4b Active / Excipient Min % Max% i) Bupropion 0.41 0.77 v) Potassium sorbate 0.03 0.05 ii) Agar 0.58 1.08 iii) Sodium alginate 0.17 0.32 iv) Magnesium chloride 0.03 0.06 vii) Citric acid 0.01 0.01 vi) Water 68.77 to 100.00

[00101] An optimum product was obtained when the ingredients were present in amounts 5 by weight or weight % as illustrated in Table 4c below and had a pH of 4.7: Table 4c Active / Excipient Mass (g) Percentage (%) i) Bupropion 0.15 0.59 v) Potassium sorbate 0.01 0.04 ii) Agar 0.21 0.83 iii) Sodium alginate 0.06 0.24 iv) Magnesium chloride 0.01 0.04 vii) Citric acid 0.00 0.01 vi) Water 25.00 98.25 Total 25.45 100.00 EXAMPLE 5

[00102] The drug Venlafaxine was formulated, and the gelling agents were found to provide a satisfactory product when the ingredients were present in amounts (weight %) as 10 illustrated in Table 5a below: Table 5a Active / Excipient Min % Max % i) Venlafaxine 0.20 0.40 v) Preservative 0.02 0.06 ii) Agar 0.40 1.10 iii) Sodium alginate 0.10 0.40 iv) Divalent Cation 0.02 0.07 vi) pH modifier 0.00 0.03 vii) Water 65.00 to 100.00

[00103] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 5b below: Table 5b Active / Excipient Min % Max % i) Venlafaxine 0.21 0.38 v) Potassium sorbate 0.03 0.05 ii) Agar 0.58 1.08 iii) Sodium alginate 0.17 0.32 iv) Magnesium chloride 0.03 0.06 vi) Citric acid 0.01 0.02 vii) Water 68.97 to 100.00

[00104] An optimum product was obtained when the ingredients were present in amounts 5 by weight or weight % as illustrated in Table 5c below and had a pH of 4.8: Table 5c Active / Excipient Mass (g) Percentage (%) i) Venlafaxine 0.08 0.30 v) Potassium sorbate 0.01 0.04 ii) Agar 0.21 0.83 iii) Sodium alginate 0.06 0.24 iv) Magnesium chloride 0.01 0.04 vi) Citric acid 0.00 0.01 vii) Water 25.00 98.53 Total 25.37 100.00 EXAMPLE 6

[00105] The drug Paracetamol was formulated, and the gelling agents were found to provide a satisfactory product when the ingredients were present in amounts (weight %) as 10 illustrated in Table 6a below: Table 6a Active / Excipient Min % Max% i) Paracetamol 0.90 1.80 v) Preservative 0.01 0.05 iv) Divalent Cation 0.01 0.05 ii) Agar 0.30 0.70 iii) Sodium alginate 0.05 0.20 vii) Water 45.00 to 100.00 viii) Solubiliser 0.00 40.00 | vi) pH modifier|0.00 |0.20 |

[00106] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 6b below: Table 6b Active / Excipient Min % Max% i) Paracetamol 0.96 1.78 v) Potassium sorbate 0.02 0.04 iv) Magnesium chloride 0.02 0.04 ii) Agar 0.33 0.60 iii) Sodium alginate 0.10 0.18 vii) Water 47.86 to 100.00 viii) Glycerol 20.71 38.47 vi) Citric acid 0.01 0.01 5

[00107] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 6c below and had a pH of 4.8: Table 6c Active / Excipient Mass (g) Percentage (%) i) Paracetamol 0.50 1.37 v) Potassium sorbate 0.01 0.03 iv) Magnesium chloride 0.01 0.03 ii) Agar 0.17 0.46 iii) Sodium alginate 0.05 0.14 vii) Water 25.00 68.37 viii) Glycerol 10.82 29.59 vi) Citric acid 0.00 0.01 Total 36.56 100.00 DEVELOPMENT AND COMPARATIVE EXAMPLES 10 Experimental series 1

[00108] Applicant explored a single gelling agent with a first exemplary class I API (Cetirizine).

[00109] The initial agar formulation was as set out in Table 7a Table 7a Active / Excipient Mass (g) % Cetirizine hydrochloride 0.01 0.04 Potassium sorbate 0.01 0.04 Agar 0.19 0.75 Water 25.00 99.17

[00110] The gel texture was semi firm, and the appearance was slightly cloudy due to agar. The agar powder used was pale yellow, which resulted in the cloudy appearance. Cetirizine and potassium sorbate are colourless (i.e. white) in comparison.

[00111] A new gelling agent, sodium alginate, was explored in combination with the agar to reduce the cloudy appearance and investigate texture options. Alginate gel formation is commonly induced by ionic bonds and electrostatic interactions between the carboxyl groups in the alginate and cations. In an aqueous solution, the monovalent ions (e.g. sodium in sodium alginate) are exchanged for divalent cations that will bind to the guluronate block of an alginate polymer chain and form a junction with another guluronate block of another alginate chain. This cross linking is referred to as the egg-box model. This changes the low viscosity solution to a gel structure. Calcium ions are the most frequently used cross-linking agent but were found to cause uncontrolled, rapid, gelation leading to heterogenous cross-linking.

[00112] By using magnesium ions, a slower gelation occurred which improved the uniformity and elasticity of the gel. A comparison of using calcium gluconate and magnesium chloride is set out in Tables 7b and 7c. Table 7b Active / Excipient Min % Max% Cetirizine hydrochloride 0.04 0.04 Potassium sorbate 0.04 0.04 Calcium gluconate 0.20 0.39 Agar 0.74 0.74 Sodium alginate 1.13 1.14 Water 97.66 97.85 Table 7c Active / Excipient Min % Max% Cetirizine hydrochloride 0.04 0.04 Potassium sorbate 0.04 0.04 Magnesium chloride 0.04 0.39 Agar 0.74 0.74 Sodium alginate 1.13 1.14 Water 97.66 98.00

[00113] Applicant found that the gels created with calcium gluconate were extremely soft and clumpy whereas the gels with magnesium chloride were firmer and more similar in appearance to the gels made with agar.

[00114] Adjustments to the magnesium chloride and sodium alginate were trialled as seen in Table 7d. The preferred values for magnesium chloride and sodium alginate were 0.04% and 0.20% respectively. Table 7d Active / Excipient Min % Max% Cetirizine hydrochloride 0.04 0.04 Potassium sorbate 0.04 0.04 Magnesium chloride 0.04 0.39 Agar 0.74 0.75 Sodium alginate 0.04 1.13 Water 97.66 99.09

[00115] Applicant revisited agar and examined lower concentrations, since sodium alginate and magnesium were added as demonstrated in Table 7e. Table 7e Active / Excipient Min % Max% Cetirizine hydrochloride 0.04 0.04 Potassium sorbate 0.04 0.04 Magnesium chloride 0.04 0.04 Agar 0.59 0.75 Sodium alginate 0.20 0.20 Water 98.93 99.09

[00116] The preferred formulation for Cetirizine was as described in Example 1, Table 1c. Experimental series 2 to 6

[00117] Applicant explored other active pharmaceutical ingredients (APIs) in the same family as Cetirizine, BCS Class I. These APIs included Doxycycline, Levetiracetam, Bupropion, Venlafaxine and Paracetamol. Experimental series 2

[00118] Doxycycline is an antibiotic that treats infections caused by bacteria and parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, and syphilis.

[00119] Based on the successful findings from Cetirizine, the same gel-base was applied to Doxycycline as illustrated in Table 8a. Table 8a Active / Excipient Mass (g) % Doxycycline 0.10 0.39 Potassium sorbate 0.01 0.04 Magnesium chloride 0.01 0.04 Agar 0.17 0.67 Sodium alginate 0.05 0.20 Water 25.00 98.66

[00120] The pH of the gel was 3.4. Instability was observed and the gel turned cloudy and fatty or waxy in appearance. This was due to the pH being close to the pKa of Doxycycline, 3.0. pH adjustment was necessary to continue working with Doxycycline.

[00121] To raise the pH of the gel, a base, sodium hydroxide, was added to the formulation. The pH values obtained ranged from 3.4 to 6.0 as illustrated in Table 8b. Table 8b Active / Excipient Min % Max% Doxycycline 0.39 0.39 Potassium sorbate 0.04 0.04 Magnesium chloride 0.04 0.04 Agar 0.67 0.67 Sodium alginate 0.20 0.20 Water 98.61 98.66 Sodium hydroxide 0.00 0.05

[00122] Gels with pH above 4.5 were promising, the cloudy and fatty layer was reduced but the texture was quite soft in comparison to Cetirizine. Agar was increased to address the issue, resulting in a preferred formulation for Doxycycline as described in Example 2, Table 2c with a pH of 4.7. Experimental series 3

[00123] Levetiracetam is a medicine used to treat epilepsy. Levetiracetam was explored with the base from Cetirizine and Doxycycline. Agar concentrations were explored from 0.47% to 0.67% as set out in Table 9a Table 9a Active / Excipient Min % Max% Levetiracetam 0.98 0.98 Potassium sorbate 0.04 0.04 Magnesium chloride 0.04 0.04 Agar 0.47 0.67 Sodium alginate 0.20 0.20 Water 98.08 98.27

[00124] This resulted in a preferred formulation for Levetiracetam as described in Example 3, Table 3c with a pH of 6.9. 5 Experimental series 4

[00125] Bupropion or amfebutamone, is an antidepressant primarily used to treat major depressive disorder, seasonable affective disorder and to support smoking cessation.

[00126] The Cetirizine gel base was applied to Bupropion as set out in Table 10a. Table 10a Active / Excipient Mass (g) % Bupropion 0.15 0.59 Potassium sorbate 0.01 0.04 Magnesium chloride 0.01 0.04 Agar 0.17 0.67 Sodium alginate 0.05 0.20 Water 25.00 98.46

[00127] The gel texture was soft, so agar and sodium alginate concentrations were increased as per Table 10b. Table 10b Active / Excipient Min % Max% Bupropion 0.59 0.59 Potassium sorbate 0.04 0.04 Magnesium chloride 0.04 0.04 Agar 0.75 0.86 Sodium alginate 0.20 0.27 Water 98.19 98.38

[00128] The pH of the gels ranged between 5.0 to 6.0. The gels with higher concentrations of agar and sodium alginate were semi-firm and slightly cloudy.

[00129] pH adjustment to more acidic pH was attempted to correct the texture and appearance. This was achieved with citric acid as illustrated in Table 10c. Table 10c Active / Excipient Min % Max% Bupropion 0.59 0.59 Potassium sorbate 0.04 0.04 Magnesium chloride 0.04 0.04 Agar 0.83 0.83 Sodium alginate 0.24 0.24 Water 98.24 98.26 Citric acid 0.00 0.02 5

[00130] The gels with higher citric acid (i.e. lower pH) had a semi-firm texture and reduced cloudiness with the preferred gel being as illustrated in Example 4, Table 4c with a pH of 4.7. Experimental series 5 10

[00131] As Venlafaxine is an antidepressant similar to Bupropion, a base formula as Bupropion was trailed as set out in Table 11a. Table 11a Active / Excipient Mass (g) % Venlafaxine 0.08 0.30 Potassium sorbate 0.01 0.04 Agar 0.21 0.83 Sodium alginate 0.06 0.24 Magnesium chloride 0.01 0.04 Citric acid 0.00 0.01 Water 25.00 98.55 15

[00132] Further, exploration with citric acid was needed to bring the pH closer to 4.0 to 4.5 as Table 11b. Table 11b Active / Excipient Min % Max % i) Venlafaxine 0.03 0.03 v) Potassium sorbate 0.04 0.04 ii) Agar 0.83 0.83 iii) Sodium alginate 0.24 0.24 iv) Magnesium chloride 0.04 0.04 vii) Citric acid 0.01 0.01 vi) Water 98.55 98.81

[00133] The preferred formulation was as set out in Example 5, Table 5c with a pH of 4.8. Experimental series 6

[00134] Paracetamol or acetaminophen is used to treat fever and mild to moderate pain. The Cetirizine base formula was applied to Paracetamol as illustrated in Table 12a. After a few hours, crystallisation of the gel was observed. This alerted the Applicant that instability was occurring within the gel. Table 12a Active / Excipient Mass % Paracetamol 0.50 1.94 Potassium sorbate 0.01 0.04 Magnesium chloride 0.01 0.04 Agar 0.17 0.66 Sodium alginate 0.05 0.19 Water 25.00 97.13

[00135] Glycerol, a solubiliser used in food applications was explored for Paracetamol. Concentrations of 15-35% were trialled as illustrated in Table 12b. High amounts of glycerol i.e. over 30% were successful in stabilising paracetamol. The pH of these gels was between 6. 0 to 7.0. Table 12b Active / Excipient Min % Max% Paracetamol 1.26 1.65 Potassium sorbate 0.03 0.03 Magnesium chloride 0.03 0.03 Agar 0.43 0.56 Sodium alginate 0.13 0.17 Water 63.13 82.56 Glycerol 14.99 35.00

[00136] Applicant found that gels, with the exception of Levetiracetam gels, with a pH between 4.0 to 5.0 had preferred textures. Accordingly, a pH adjustment was conducted to bring the pH of the Paracetamol gels down using citric acid as set out in Table 12c. Active / Excipient Min % Max% Paracetamol 1.37 1.65 Potassium sorbate 0.03 0.03 Magnesium chloride 0.03 0.03 Agar 0.46 0.56 Sodium alginate 0.14 0.17 Water 68.29 82.56 Glycerol 29.55 35.73 Citric acid 0.00 0.14

[00137] The preferred formulation is as illustrated in Example 6, Table 6c with the presence of the glycerol preventing crystallisation of the Paracetamol. The pH was 4.8.

Claims

1. A pharmaceutical formulation comprising:i) a Biopharmaceutics Classification System (BCS) class I Active Pharmaceutical Ingredient (API), or a salt or solution thereof,ii) a primary gelling agent which is agar;iii) a secondary gelling agent which is an alginate;iv) at least one cation donator,v) a preservative, andvi) water.

2. A pharmaceutical formulation as claimed in claim 1 which further comprises one or more of:vii) a pH modifier, andviii) a solubiliser.

3. A pharmaceutical formulation as claimed in any of the preceding claims wherein the API is Cetirizine, Doxycycline, Levetiracetam, Bupropion, Venlafaxine, Paracetamol, or a salt or solution thereof.

4. A pharmaceutical formulation as claimed in any of claims 1 to 3 wherein the ratio of agar to alginate is from 1.6:1 to 5.6:1.

5. A pharmaceutical formulation as claimed in claim 4 wherein the ratio of agar to alginate is from 2.4:1 to 5.2:1.

6. A pharmaceutical formulation as claimed in claim 4 or 5 wherein the agar is present in an amount, by weight %, of from 0.30 to 1.4 and the alginate is present in an amount, by weight %, of from 0.05 to 0.4.

7. A pharmaceutical formulation as claimed in claim 6 wherein the agar is present in an amount, by weight %, of from 0.33 to 1.08 and the alginate is present in an amount, by weight %, of from 0.10 to 0.32.

8. A pharmaceutical formulation as claimed in any of claims 1 to 7 wherein iv) the cation donator is a divalent cation.

9. A pharmaceutical formulation as claimed in any of claims 8 wherein iv) the divalent cation is magnesium.

10. A pharmaceutical formulation as claimed in claim 8 or 9 wherein ratio of alginate to divalent cation, by weight %, is from 3:1 to 7:1.

11. A pharmaceutical formulation as claimed in claim 10 wherein the divalent cation is present in an amount, by weight %, of from 0.01 to 0.07.

12. A pharmaceutical formulation as claimed in any of claims 1 to 11 wherein v) the preservative is potassium sorbate.

13. A pharmaceutical formulation as claimed in any of claims 1 to 12 wherein vii) the pH modifier is one of sodium hydroxide or citric acid.

14. A pharmaceutical formulation as claimed in claim 13 wherein the pH is between 4.0 and 7.5.

15. A pharmaceutical formulation as claimed in any of claims 1 to 14 wherein viii) the solubiliser is glycerol.

16. A pharmaceutical formulation as claimed in claim 3 whereini) the API is Cetirizine or a salt or solution thereof.

17. A pharmaceutical formulation as claimed in claim 16 whereini) the salt is a hydrochloride.

18. A pharmaceutical formulation as claimed in claim 16 or 17 wherein the formulation comprises ingredients (by weight %) in the range as Table 1a.Table 1aActive / Excipient Min % Max% i) Cetirizine hydrochloride 0.02 0.06 v) Preservative 0.02 0.06 iv) Divalent cation 0.02 0.06 ii) Agar 0.40 0.90 iii) Sodium alginate 0.10 0.30 vi) Water 65.00 to 100.0019. A pharmaceutical formulation as claimed in claim 18 wherein the formulation comprises ingredients (by weight %) in the range as Table 1b.Table 1bActive / Excipient Min % Max% i) Cetirizine hydrochloride 0.03 0.05 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.06 ii) Agar 0.47 0.88 iii) Sodium alginate 0.14 0.26 vi) Water 69.30 to 100.0020. A pharmaceutical formulation as claimed in claim 18 or 19 wherein the formulation5 comprises ingredients (by weight (g) or weight %) as set out in Table 1c.Table 1cActive / Excipient Mass (g) Percentage (%) i) Cetirizine hydrochloride 0.01 0.04 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.17 0.67 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 99.01 Total 25.25 100.0021. A pharmaceutical formulation as claimed in claim 3 whereini) the API is Doxycycline or a salt or solution thereof.

22. A pharmaceutical formulation as claimed in claim 21 wherein the formulation comprises ingredients (by weight %) in the range as Table 2a.Table 2aActive / Excipient Min % Max% i) Doxycycline 0.20 0.60 v) Preservative 0.02 0.10 iv) Divalent cation 0.02 0.06 ii) Agar 0.45 1.40 iii) Sodium alginate 0.10 0.40 vi) Water 65.00 to 100.00 vii) pH modifier 0.00 0.0523. A pharmaceutical formulation as claimed in claim 22 wherein the formulation comprises ingredients (by weight %) in the range as Table 2b.Table 2bActive / Excipient Min % Max% i) Doxycycline 0.28 0.51 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.05 ii) Agar 0.55 1.02 iii) Sodium alginate 0.14 0.26 vi) Water 68.97 to 100.00 vii) Sodium hydroxide 0.01 0.035 24. A pharmaceutical formulation as claimed in claim 22 or 23 wherein the formulationcomprises ingredients (by weight (g) or weight %) as set out in Table 2c.Table 2cActive / Excipient Mass (g) Percentage (%) i) Doxycycline 0.10 0.39 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.20 0.79 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 98.52 vii) Sodium hydroxide 0.01 0.02 Total 25.38 100.0025. A pharmaceutical formulation as claimed in claim 3 wherein the API is Levetiracetam or a salt or solution thereof.

26. A pharmaceutical formulation as claimed in claim 25 wherein the formulation comprises ingredients (by weight %) in the range as Table 3a.Table 3aActive / Excipient Min % Max% i) Levetiracetam 0.60 1.30 v) Preservative 0.02 0.06 iv) Divalent Cation 0.02 0.06 ii) Agar 0.46 0.90 iii) Sodium alginate 0.10 0.30 vi) Water 65.00 to 100.0027. A pharmaceutical formulation as claimed in claim 26 wherein the formulation comprises ingredients (by weight %) in the range as Table 3b.Table 3bActive / Excipient Min % Max% i) Levetiracetam 0.69 1.28 v) Potassium sorbate 0.03 0.05 iv) Magnesium chloride 0.03 0.05 ii) Agar 0.47 0.87 iii) Sodium alginate 0.14 0.26 vi) Water 68.65 to 100.005 28. A pharmaceutical formulation as claimed in claim 26 or 27 wherein the formulationcomprises ingredients (by weight (g) or weight %) as set out in Table 3c.Table 3cActive / Excipient Mass (g) Percentage (%) i) Levetiracetam 0.25 0.98 v) Potassium sorbate 0.01 0.04 iv) Magnesium chloride 0.01 0.04 ii) Agar 0.17 0.67 iii) Sodium alginate 0.05 0.20 vi) Water 25.00 98.08 Total 25.49 100.0029. A pharmaceutical formulation as claimed in claim 3 wherein the API is Bupropion or a salt or solution thereof.

30. A pharmaceutical formulation as claimed in claim 29 wherein the formulation comprises ingredients (by weight %) in the range as Table 4a.Table 4aActive / Excipient Min % Max% i) Bupropion 0.40 0.80 v) Preservative 0.02 0.06 ii) Agar 0.40 1.10 iii) Sodium alginate 0.10 0.40 iv) Divalent cation 0.02 0.07 vii) pH modifier 0.00 0.02 vi) Water 65.00 to 100.0031. A pharmaceutical formulation as claimed in claim 30 wherein the formulation comprises ingredients (by weight %) in the range as Table 4b.Table 4bActive / Excipient Min % Max % i) Bupropion 0.41 0.77 v) Potassium sorbate 0.03 0.05 ii) Agar 0.58 1.08 iii) Sodium alginate 0.17 0.32 iv) Magnesium chloride 0.03 0.06 vii) Citric acid 0.01 0.01 vi) Water 68.77 to 100.0032. A pharmaceutical formulation as claimed in claim 29 or 30 wherein the formulation5 comprises ingredients (by weight (g) or weight %) as set out in Table 4c.Table 4cActive / Excipient Mass (g) Percentage (%) i) Bupropion 0.15 0.59 v) Potassium sorbate 0.01 0.04 ii) Agar 0.21 0.83 iii) Sodium alginate 0.06 0.24 iv) Magnesium chloride 0.01 0.04 vii) Citric acid 0.00 0.01 vi) Water 25.00 98.25 Total 25.45 100.0033. A pharmaceutical formulation as claimed in claim 3 wherein the API is Venlafaxine or a salt or solution thereof.10 34. A pharmaceutical formulation as claimed in claim 33 wherein the formulationcomprises ingredients (by weight %) in the range as Table 5a.Table 5aActive / Excipient Min % Max% i) Venlafaxine 0.20 0.40 v) Preservative 0.02 0.06 ii) Agar 0.40 1.10 iii) Sodium alginate 0.10 0.40 iv) Divalent Cation 0.02 0.07 vi) pH modifier 0.00 0.03 vii) Water 65.00 to 100.0035. A pharmaceutical formulation as claimed in claim 34 wherein the formulation comprises ingredients (by weight %) in the range as Table 5b.Table 5bActive / Excipient Min % Max% i) Venlafaxine 0.21 0.38 v) Potassium sorbate 0.03 0.05 ii) Agar 0.58 1.08 iii) Sodium alginate 0.17 0.32 iv) Magnesium chloride 0.03 0.06 vi) Citric acid 0.01 0.02 vii) Water 68.97 to 100.0036. A pharmaceutical formulation as claimed in claim 34 or 35 wherein the formulation5 comprises ingredients (by weight (g) or weight %) as set out in Table 5c.Table 5cActive / Excipient Mass (g) Percentage (%) i) Venlafaxine 0.08 0.30 v) Potassium sorbate 0.01 0.04 ii) Agar 0.21 0.83 iii) Sodium alginate 0.06 0.24 iv) Magnesium chloride 0.01 0.04 vi) Citric acid 0.00 0.01 vii) Water 25.00 98.53 Total 25.37 100.0037. A pharmaceutical formulation as claimed in claim 3 wherein the API is Paracetamol or a salt or solution thereof.10 38. A pharmaceutical formulation as claimed in claim 37 wherein the formulationcomprises ingredients (by weight %) in the range as Table 6a.Table 6aActive / Excipient Min % Max % i) Paracetamol 0.90 1.80 v) Preservative 0.01 0.05 iv) Divalent Cation 0.01 0.05 ii) Agar 0.30 0.70 iii) Sodium alginate 0.05 0.20 vii) Water 45.00 to 100.00 viii) Solubiliser 0.00 40.00 vi) pH modifier 0.00 0.2039. A pharmaceutical formulation as claimed in claim 38 wherein the formulation comprises ingredients (by weight %) in the range as Table 6b.Table 6bActive / Excipient Min % Max % i) Paracetamol 0.96 1.78 v) Potassium sorbate 0.02 0.04 iv) Magnesium chloride 0.02 0.04 ii) Agar 0.33 0.60 iii) Sodium alginate 0.10 0.18 vii) Water 47.86 to 100.00 viii) Glycerol 20.71 38.47 vi) Citric acid 0.01 0.0140. A pharmaceutical formulation as claimed in claim 38 or 39 wherein the formulation5 comprises ingredients (by weight (g) or weight %) as set out in Table 6c.Table 6cActive / Excipient Mass (g) Percentage (%) i) Paracetamol 0.50 1.37 v) Potassium sorbate 0.01 0.03 iv) Magnesium chloride 0.01 0.03 ii) Agar 0.17 0.46 iii) Sodium alginate 0.05 0.14 vii) Water 25.00 68.37 viii) Glycerol 10.82 29.59 vi) Citric acid 0.00 0.01 Total 36.56 100.00

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