Pharmaceutical formulations

Abstract

This invention relates to a pharmaceutical formulation and more particularly to one for Active Pharmaceutical Ingredients (APIs) which are recognised under the Biopharmaceutical Classification System (BCS) as a Class I, III or III drug. In addition to the API, it comprises a combination of gelling agents comprising: a primary gelling agent which is agar and a secondary gelling agent which is an alginate together with at least one cation donator, a preservative, and water and optionally a thickening agent, sweetener(s) and flavouring.

Description

PHARMACEUTICAL FORMULATIONS

[0001] This invention relates to pharmaceutical formulations and more particularly to one’s for Active Pharmaceutical Ingredients (APIs) which are recognised under the Biopharmaceutical Classification System (BCS) as a Class I, Class II or Class III 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 .0 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] Additionally, an API can also refer to isolated, purified or standardised versions of vitamins, minerals, herbal extracts or supplements that provide a therapeutic effect such as curing, treating or preventing disease. These APIs must meet strict quality and purity standards such as following Good Manufacturing Practice (GMP) and meeting specifications outlined in pharmacopeias like the United States Pharmacopeia (USP).

[0014] The dosage form may be used in human or animal health.

[0015] 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 , WG2024028788 and WO2024134616.

[0016] Other background art identified includes:

[0017] EP 1238663 A2 which discloses a binary system consisting of two hydrophilic polymers comprising agar and alginate or chitosan. The procedure consists of preparing the two gels separately which are mixed by titration when prepared.

[0018] US 2008 / 0274188 A1 which discloses an oral vehicle called a Bolus Semi-Solid Gel (BSSG) for delivery active ingredients using a semi-solid agar gel unit dose that comprises about 0.1% to 10% by weight of agar, with a hardness from 1 to 15 N / mm.

[0019] WO 02 / 064120 A1 which discloses an edible gel containing two medical components; a first edible gel component which is broken down in the stomach and a second edible gel component which is broken down in the intestinal tract.

[0020] WO 2008 / 122993 A1 which discloses a controlled-release oral pharmaceutical comprising of microparticles with a core containing API(s), one or more coating layers (pH- independent and optionally pH-dependent polymers) and optional in-situ gelling agents and cross-linkers to allow composition to be reconstituted as a suspension.

[0021] ON 110833561 A which discloses a chewable omeprazole tablet.

[0022] ON 111437261 A which discloses a chewable idecalcidol tablet.

[0023] 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. These, new formulations, like Applicants’ referenced formulations are drinkable gels, delivered in an amount of typically 10 to 50 mL, more preferably 20 to 50 mL (or g), which when sucked from e.g. a pouch, shear making them drinkable.

[0024] The term “drinkable” is herein interchangeable with drink, suck, suckable, squeeze, and squeezable.

[0025] “Drinkable” refers to mechanical disruption of the set gel to a flowable mass that is swallowable without chewing by the application of an external force that may include, but not be limited to, the application of a negative pressure applied to a nozzle, straw, or spout (sucking), a positive pressure applied to a container attached to or comprising a syringe, nozzle, straw, or spout (squeezing), stirring or scooping with a spoon from an open container.

[0026] 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.

[0027] 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.

[0028] Cetirizine is a second generation antihistamine, see

[0029] Branded versions include Allacan, Piriteze, and Zyrtec.

[0030] Doxycycline is a broad-spectrum antibiotic of the tetracycline class used in the treatment of infections caused by bacteria and certain parasites, see

[0031] Branded forms include Doryx, and Vibramycin.

[0032] Levetiracetam is a medication used to treat epilepsy, seeLwiki / Leyeti raceta .

[0033] Branded forms include Keppra, Elepsia, and Spritam.

[0034] 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.

[0035] Branded forms include Wellbutrin and Zyban.

[0036] Venlafaxine is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, see https: / / en.wikipedia.org / wiki / Venlafaxine.

[0037] Branded forms include Effexor, Efexor XR, and Venbysi XR.

[0038] Paracetamol (acetaminophen) is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain, see https ;7e n wi k i ped i a o rg / wiki / Pa racetamp i .

[0039] Branded forms include Tylenol and Panadol.

[0040] Furthermore, alternative pharmaceutical formulations for BCS Class II and III drugs, as exemplified by, for example, (1) Ibuprofen, (2) Naproxen, and (3) Metformin were achieved.

[0041] Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain, fever and inflammation, see https: / / en.wikipedia.org / wiki / ibuprofen.

[0042] Branded forms include Advil, Nurofen and Motrin.

[0043] Naproxen is a also an NSAID used to treat conditions such as pain, menstrual cramps, arthritis and fever, see https: / / en.wikipedia.org / wiki / Naproxen.

[0044] Branded forms include Aleve, Flanax, Naprogesic, and Naprosyn.

[0045] Metformin is used for the treatment of type 2 diabetes and polycystic ovary syndrome (PCOS), see h ftps : / / en . wi ki ped I a . o rq / wi ki / M etf o rm i n .

[0046] Branded forms include Glucophage, Diabex, Diaformin, and Metex.

[0047] 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: h ftps : / / www .fda.qov / media / 156350 / down load incorporated by reference.BRIEF SUMMARY OF THE DISCLOSURE

[0048] In accordance with the present inventions there is provided a pharmaceutical formulation, for Active Pharmaceutical Ingredients (APIs) spanning Biopharmaceutical Classification System (BCS) Class I, II and III, comprising: i) one or more Biopharmaceutical Classification System (BCS) Class I, II or III 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.

[0049] Preferably the formulation further comprises one or more of: vii) a pH modifier, viii) a solubiliser, ix) one or more sweetener(s), x) a flavouring, and xi) a thickening agent.

[0050] The addition of a thickening agent, preferably xanthan gum in an amount by wt % of from 0.1 to 0.4%, proved to be desirable for embodiments where the gel showed a tendency for syneresis in storage, handling and / or shelf-life.

[0051] With drinkable gels, which contain water, syneresis can prove challenging, and indeed Applicant determined that for formulations comprising the 2 gelling agents in the amounts used in the 25 to 37mL (or g) embodiments it was desirable to further add a thickening agent, e.g. xanthan gum, in the amount 0.1 to 0.4% to address the syneresis.

[0052] Of course, alternative thickening agents might be used in appropriate amounts. Such alternative thickening agents include starch (e.g. arrowroot, corn starch, modified starch, potato starch, tapioca starch), gums (e.g. acacia gum, gum arabic, gellan gum, guar gum, locust bean gum), as well as gelatine, and cellulose derivatives (e.g. methylcellulose).

[0053] Non-limiting examples of textured formulations comprising APIs representative of different BCS classes include (by USAN naming) Cetirizine, Doxycycline, Levetiracetam, Bupropion, Venlafaxine, Paracetamol (a BCS Class I API), or a salt or solution thereof, Ibuprofen, Naproxen (a BCS Class II API), or a salt or solution thereof, and Metformin (a BCS Class III API), or a salt or solution thereof.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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 32sto 45sC that does not melt below 85sC. 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.

[0058] However, to accommodate different Class I APIs it proved necessary to incorporate a secondary gelling agent.

[0059] The secondary gelling agent is an alginate. The alginates include:• Sodium alginate (NaCsHyOs),• Potassium alginate (KCeHyOs), and• Calcium alginate (CaCigH Oig).

[0060] Following extensive studies Applicant determined not only were two specific gelling agents required, but it was necessary to control their relative amounts, and where formulations showed syneresis, the addition of a thickening agent, preferably xanthan gum, in amounts of 0.1 to 0.4% was required to overcome the technical challenge of syneresis.

[0061] Other minor changes to the amounts of other ingredients present, and minor changes in pH also proved desirable.

[0062] 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 .

[0063] Where proportionally more water is added to the agar / alginate formulation, such that syneresis may occur, it is desirable to add a thickening agent, e.g. xanthan gum, and increase the upper level of Alginate from 5.6:1 to 6.5:1 and from 5.2:1 to 6:25.

[0064] 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.

[0065] Where proportionally more water is added to the agar / alginate formulation, such that syneresis may occur, it is desirable to add a thickening agent, e.g. xanthan gum, and increase the upper level of agar from 1.40% to 1 .50% and the upper level of alginate from 0.40% to 0.45%.

[0066] 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.

[0067] Where proportionally more water is added to the agar / alginate formulation, such that syneresis may occur, it is desirable to add a thickening agent, e.g. xanthan gum, and increase to increase the upper level of agar from 1 .08% to 1 .40% and alginate from 0.32% to 0.40%.

[0068] The preferred agar is agar-agar and the preferred alginate is sodium alginate.

[0069] To facilitate gelling the cation donator is a divalent cation which facilitates cross linking of the alginate.

[0070] Preferably the iv) at least one divalent cation is calcium or magnesium, offered as a salt.

[0071] In a preferred embodiment the iv) cation donator is magnesium chloride.

[0072] 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 .

[0073] The amount, by weight %, of the divalent cation (measured as the weight of the salt) is from 0.01 to 0.07.

[0074] Preferably the v) at least one preservative is selected from lactic acid, potassium sorbate, sorbic acid and sodium benzoate.

[0075] In a preferred embodiment the formulation comprising a BCS API has as v) the at least one preservative, potassium sorbate.

[0076] 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, sodium bicarbonate, sodium citrate and sodium hydroxide.

[0077] The pH is in general controlled to be between 4.0 and 7.5. The preferred pH is selected based on:• the reference to physiological function of the API,• the solubility of the API in aqueous solution and its form when encapsulated or carried in the gel, and• the pKa of the API.

[0078] 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

[0079] For embodiments where the water volume increases to make a 40 mL drinkable gel, and a thickening agent added to address the syneresis resulting from higher water concentrations, the pH may also be altered as follows:• Cetirizine pH 4.4 to 5.4, preferably pH 4.9• Ibuprofen pH 6.5 to 7.5, preferably pH 7.0• Naproxen pH 6.5 to 7.5, preferably pH 7.0 and• Metformin pH 4.3 to 5.3, preferably pH 4.8

[0080] In some embodiments it is desirable to include a solubilising agent.

[0081] One such solubilising agent is glycerol.

[0082] For embodiments where the water volume increases to make a 40 mL drinkable gel and a thickening agent added to address the syneresis resulting from higher water concentrations, it is desirable to include: at least one sweetener.

[0083] One such sweetener is sucralose and / or sorbitol.

[0084] 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 2.6% by weight.

[0085] Flavouring can refer to sweet, salty, sour, bitter, umami, floral, herbal, woody, fresh, earthy or spice flavours.

[0086] Preferred flavourings include fruit flavours e.g. blood orange, grape or an essential oil (e.g. menthol).

[0087] In some embodiments, namely those with additional water as exemplified by the 40 mL embodiments, it is desirable to include xii) a thickening agent, more particularly one which counters any residual syneresis that may occur using the specified gel combination.

[0088] A preferred thickening agent is xanthan gum, which may be incorporated in an amount by % of from 0.1 to 0.4% and replaces a corresponding amount of water.

[0089] The actual amounts vary with the particular API selected.

[0090] With respect to the weight percent figures, for “generic” claims these are based on the essential components specified and exclude optional excipients. However, for specific drug formulations they include all identified excipients.

[0091] In a first embodiment the API is BCS Class I API is e.g. Cetirizine or a salt or solution thereof.

[0092] Preferably the salt is a hydrochloride.

[0093] An exemplary BCS Class I formulation is illustrated where the API is Cetirizine and comprises ingredients (by weight %) in the range as set out in Table 1 a.Table 1a

[0094] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 1 b.Table 1b

[0095] 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

[0096] In a second embodiment the API is Doxycycline or a salt or solution thereof.

[0097] The Doxycycline formulation comprises ingredients (by weight %) in the range as set out in Table 2a.Table 2a

[0098] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 2b.Table 2b

[0099] 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

[0100] In a third embodiment the API is Levetiracetam or a salt or solution thereof.

[0101] The Levetiracetam formulation comprises ingredients (by weight %) in the range as set out in Table 3a.Table 3a

[0102] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 3b.Table 3b

[0103] 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

[0104] In a fourth embodiment the API is Bupropion or a salt or solution thereof.

[0105] The Bupropion formulation comprises ingredients (by weight %) in the range as set out in Table 4a.Table 4a

[0106] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 4b.Table 4b

[0107] Most preferably still the formulation comprises ingredients (by weight (g) or weight%) as set out in Table 4c and had a pH of 4.7.Table 4c

[0108] In a fifth embodiment the API is Venlafaxine or a salt or solution thereof.

[0109] The Venlafaxine formulation comprises ingredients (by weight %) in the range as set out in Table 5a.Table 5a

[0110] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 5b.Table 5b

[0111] Most preferably still the formulation comprises ingredients (by weight (g) or weight%) as set out in Table 5c and had a pH of 4.8.Table 5c

[0112] In a sixth embodiment the API is Paracetamol or a salt or solution thereof.

[0113] The Paracetamol formulation comprises ingredients (by weight %) in the range as set out in Table 6a.Table 6a

[0114] More preferably the formulation comprises ingredients (by weight %) in the range as set out in Table 6b.Table 6b

[0115] Most preferably still the formulation comprises ingredients (by weight (g) or weight%) as set out in Table 6c and had a pH of 4.8.Table 6c

[0116] Where the amount of the two gelling agents remains as per the embodiments above, but the volume of water is increased to provide a drinkable gel of e.g. 40 mL, the amounts of ingredients may be replaced as set out in Tables 14 to 19 (for BCS Class I formulations), Tables 20 and 21 (for BCS Class II formulations) and Tables 22 (for BCS Class III formulations).

[0117] In a favoured embodiment the pharmaceutical formulation further comprises viii) a thickening agent to address syneresis in formulations containing a higher water content relative to the gelling agents.

[0118] A preferred thickening agent is xanthan gum, which is most preferably present in an amount of from 0.1 to 0.4 % by wt.

[0119] The inclusion of a thickening agent is dependent upon the amount of the primary and secondary gelling agents (agar and alginate) and the amount of water added to form the drinkable gel formulation.

[0120] For formulations of about 25g and about 35g in the case of paracetamol (Example6) a thickening agent was not necessary, and a preferred generic formulation is illustrated in Table 23.

[0121] For formulations containing proportionally more water, e.g. those made up to about 40g (Experimental series 7) a generic formulation is preferably as illustrated in Table 24 and additionally contains a thickening agent.

[0122] Preferred formulations containing a thickening agent are illustrated below.

[0123] In one series of embodiments the API is a BCS class I API.

[0124] One such BCS class I API is Cetirizine or a salt or solution thereof.

[0125] The preferred salt is a hydrochloride.

[0126] This series of embodiments are illustrated in the formulations of Table 14a, Table 14b, Table 14c and Table 14d:

[0127] In another series of embodiments, the API is Doxycycline or a salt or solution thereof.

[0128] This series of embodiments are illustrated in the formulations of Table 15a andTable 15b:

[0129] In another series of embodiments, the API is Levetiracetam or a salt or solution thereof.

[0130] This series of embodiments are illustrated in the formulations of Table 16a andTable 16b.

[0131] In another series of embodiments, the API is Bupropion or a salt or solution thereof.

[0132] This series of embodiments are illustrated in the formulations of Table 17c andTable 17d.

[0133] In another series of embodiments, the API is Venlafaxine or a salt or solution thereof.

[0134] This series of embodiments are illustrated in the formulations of Table 18a and Table 18b.

[0135] In another series of embodiments, the API is Paracetamol or a salt or solution thereof.

[0136] This series of embodiments are illustrated in the formulations of Table 19a and Table 19b.

[0137] In another series of embodiments, the API is BCS class II API.

[0138] One such BCS class II API is Ibuprofen or a salt or solution thereof.

[0139] In the example it is a sodium salt.

[0140] This series of embodiments are illustrated in the formulations of Tables 20a, Table 20b, Table 20c, and Table 20d.

[0141] Another such BCS class II API is Naproxen or a salt or solution thereof.

[0142] In the example it is a sodium salt.

[0143] This series of embodiments are illustrated in the formulations of Tables 21a,Table 21b, Table 21c, and Table 21d.

[0144] In another series of embodiments, the API is BCS class III API.

[0145] One such BCS class III API is Metformin or a salt or solution thereof.

[0146] In the example it is a hydrochloride salt.

[0147] This series of embodiments are illustrated in the formulations of Tables 22a, Table 22b, Table 22c, and Table 22d.

[0148] The invention is further described, by way of example only, with reference to the drawing, Examples and detailed description given below.BRIEF DESCRIPTION OF THE DRAWINGS

[0149] 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

[0150] In developing a formulation for BCS Class I API’s, Applicant undertook a series of experiments and overcame a number of technical challenges.

[0151] 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.

[0152] Each of the Examples was prepared using the methodology set out below:Method

[0153] Add the API (e.g. Cetirizine, Doxycycline, Levetiracetam, Bupropion, Venlafaxine, Paracetamol, Ibuprofen, Naproxen or Metformin), 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, sodium citrate, sodium bicarbonate 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 where applicable, add the thickening agent such as xanthan gum and mix until completely dissolved. Finally, optionally add the flavouring and mix until 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. The pouch facilitates delivery of the dosage form, which is a drinkable gel which shears on sucking.EXAMPLE 1

[0154] 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

[0155] A preferred product was obtained when the ingredients were present in amounts(weight %) as illustrated in Table 1 b below:Table 1b

[0156] 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 1cEXAMPLE 2

[0157] The drug Doxycycline 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 2a below:

[0158] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 2b below:Table 2b

[0159] 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 2cEXAMPLE 3

[0160] The drug Levetiracetam 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 3a below:Table 3a

[0161] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 3b below:Table 3b

[0162] 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 3cEXAMPLE 4

[0163] The drug Bupropion 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 4a below:Table 4a| vi) Water _ | _ 65.00 | to 100.00 |

[0164] A preferred product was obtained when the ingredients were present in amounts (weight %) as illustrated in Table 4b below:Table 4b

[0165] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 4c below and had a pH of 4.7:Table 4cEXAMPLE 5

[0166] 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 illustrated in Table 5a below:Table 5a| vi) Water _ | _ 65.00 | to 100.00 |

[0167] A preferred product was obtained when the ingredients were present in amounts(weight %) as illustrated in Table 5b below:Table 5b

[0168] An optimum product was obtained when the ingredients were present in amounts by weight or weight % as illustrated in Table 5c below and had a pH of 4.8:Table 5cEXAMPLE 6

[0169] 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 illustrated in Table 6a below:Table 6a

[0170] A preferred product was obtained when the ingredients were present in amounts(weight %) as illustrated in Table 6b below:Table 6b

[0171] 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 6cDEVELOPMENT AND COMPARATIVE EXAMPLES Experimental series 1

[0172] Applicant explored a single gelling agent with a first exemplary class I API (Cetirizine).

[0173] The initial agar formulation was as set out in Table 7a

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] Applicant revisited agar and examined lower concentrations, since sodium alginate and magnesium were added as demonstrated in Table 7e.

[0180] The preferred formulation for Cetirizine was as described in Example 1 , Table 1c.Experimental series 2 to 6

[0181] 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

[0182] 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.

[0183] Based on the successful findings from Cetirizine, the same gel-base was applied to Doxycycline as illustrated in Table 8a.

[0184] 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.

[0185] 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.

[0186] 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

[0187] 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

[0188] This resulted in a preferred formulation for Levetiracetam as described inExample 3, Table 3c with a pH of 6.9.Experimental series 4

[0189] Bupropion or amfebutamone, is an antidepressant primarily used to treat major depressive disorder, seasonable affective disorder and to support smoking cessation.

[0190] The Cetirizine gel base was applied to Bupropion as set out in Table 10a.

[0191] The gel texture was soft, so agar and sodium alginate concentrations were increased as per Table 10b.

[0192] 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.

[0193] 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.

[0194] 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

[0195] As Venlafaxine is an antidepressant similar to Bupropion, a base formula as Bupropion was trailed as set out in Table 11 a.

[0196] Further, exploration with citric acid was needed to bring the pH closer to 4.0 to 4.5 as Table 11b.

[0197] The preferred formulation was as set out in Example 5, Table 5c with a pH of 4.8.Experimental series 6

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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. Experimental series 7 (Larger volume and thickening agent)

[0202] In the previous experimental series, the total product volume was between 25 to 30 mL (or g), as exemplified for Cetirizine in Table 1c, Doxycycline in Table 2c, Levetiracetam in Table 3c, Bupropion in Tables 4c, Venlafaxine in Table 5c and except for Paracetamol in Table 6c totalling to 37 mL (or g).

[0203] Applicant desired to increase the product size to 40 mL (or g).

[0204] To achieve this, Applicant increased the water volume whilst keeping the other active / excipients at the same concentrations.

[0205] It was observed that syneresis occurred in a Cetirizine prototype, with a pH of 4.9, as illustrated in Table 13a below.

[0206] Accordingly, Applicant undertook some experiments to determine whether the addition of a thickening agent would address the syneresis. They selected xanthan gum and added it at different concentrations.

[0207] Xanthan gum is a high molecular weight polysaccharide produced by Xanthomonas campestris through microbial fermentation. It is widely used in pharmaceutical applications as a hydrophilic polymer and rheology modifier in various dosage forms including oral liquids, suspensions, topical gels and controlled release products. Its primary function includes thickening, stabilising and controlling drug release.

[0208] Xanthan gum has a cellulose-like backbone composed of p-(1-4)-D-glucose units with repeating trisaccharide side chains consisting of mannose-glucuronic acid-mannose, attached to alternate glucose residues. Some mannose units are acetylated while others are substituted with pyruvic acid residues. The carboxyl and pyruvate groups impart a negative charge contributing to the high-water solubility and electrostatic interactions with other excipients.

[0209] Upon contact with water, xanthan gum rapidly hydrates due to its numerous hydroxyl and carboxyl groups, forming a viscous pseudoplastic solution. The polymer chains expand and become entangled, creating a three-dimensional network that immobilises water molecules and increases viscosity. This network is responsible for the thickening effect.

[0210] The experiment in Table 13b incorporated xanthan gum at 0.01% as a thickening agent. The gel still exhibited syneresis.

[0211] Applicant therefore investigated varying amounts of xanthan gum as illustrated inTable 13c.

[0212] The preferred gels were achieved when xanthan gum was present between 0.1% to 0.4%. Minimal syneresis was observed within this range. The gel at the highest concentration of 0.5% reduced syneresis but was difficult to incorporate with the other excipients. The preferred concentration of xanthan gum was 0.2%.

[0213] Due to the addition of water and xanthan gum, it proved desirable to increase the flavouring to account for the higher product volume. Applicant found that flavouring between 0.01% and 2.6% was acceptable depending on the final flavour selected. The preferred generic and specific ranges for a 40 mL (or g) product containing API are illustrated in Tables 14a and 14b below.

[0214] Based on the above the Cetirizine Dihydrochloride gels of Tables 14c and 14d were reformulated as 40 mL (or g) drinkable gels, delivered via a pouch at a pH of 4.9.

[0215] Based on the above the Doxycycline gels of the earlier embodiments were reformulated as 40 mL (or g) drinkable gels, delivered via a pouch at a pH of 4.7 - see Tables 15a and 15b below.

[0216] Based on the above the Levetiracetam gels of the earlier embodiments were reformulated as 40 mL (or g) drinkable gels, delivered via a pouch at a pH of 6.9 - see Tables 16a and 16b below.

[0217] Based on the above the Bupropion gels of the earlier embodiments were reformulated as 40 mL (or g) drinkable gels, delivered via a pouch at a pH of 4.7 - see Tables 17a and 17b below.

[0218] Based on the above the Venlafaxine gels of the earlier embodiments were reformulated as 40 mL (or g) drinkable gels, delivered via a pouch at a pH of 4.8 - see Tables 18a and 18b below.

[0219] Based on the above the Paracetamol gels of the earlier embodiments were reformulated as 40 mL (or g) drinkable gels, delivered via a pouch at a pH of 4.8 - see Tables 19a and 19b below.Experimental series 8 (BCS Class II and III)

[0220] Applicant further explored whether the formulation would work with BCS Class II and III APIs using Ibuprofen and Naproxen as exemplary BCS class II drugs and Metformin as an exemplary BCS class III drug, using the % ranges in Table 14a with the exemplary BCS class I API being replaces with a BCS class II or III API.

[0221] The experiments were successful as Applicant was able to use the generic Table14a formulation to create homogenous and smooth textured gels whilst maintaining product stability for the exemplary BCS Class II and III drugs.

[0222] Two BCS class II drug formulations are illustrated in Tables 20a to 20d (Ibuprofen) and Tables 21a to 21 d (Naproxen) where Tables 20a and 21a illustrate generically max and min concentrations of ingredients, Tables 20b and 21b identify preferred functional ingredients and Tables 20c, 20d, 21c and 21 d illustrate specific embodiments with a pH of 7.0.

[0223] A single illustrative example of a BCS Class III drug, formulated as a 40 mL (or g) drinkable gel, is exemplified by Metformin. Table 22a illustrates generically max and minconcentrations of ingredients. Table 22b identifies preferred functional ingredients and Tables 22c and 22d illustrate specific embodiments with a pH of 4.8.

[0224] Based on each of the Examples the final amounts of ingredients in part depends on the minimum / maximum amount of API and the volume of the final formulation.

[0225] The broadest “generic” formulation for a 24 to 26 mL (or g) formulation (and 35 to 37 mL or g) in the case of the Paracetamol example - Table 6) is illustrated in Table 23 and for one made up to 40 mL (or g) (with additional water added together with flavouring, sweetener(s) and a thickening agent) is illustrated in Table 24.

Claims

CLAIMS1 . A pharmaceutical formulation for Active Pharmaceutical Ingredients (APIs) spanning Biopharmaceutical Classification System (BCS) Class I, II and III comprising: i) one or more Biopharmaceutical Classification System (BCS) Class I, II or III 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.

2. A pharmaceutical formulation as claimed in claim 1 which further comprises one or more of: vii) a pH modifier, viii) a solubiliser, ix) at least one sweetener, x) a flavouring, and xi) a thickening agent.

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

4. A pharmaceutical formulation as claimed in claim 1 or 2 wherein the BCS Class II API is selected from Ibuprofen, Naproxen or a salt or solution thereof.

5. A pharmaceutical formulation as claimed in claim 1 or 2 wherein the BCS Class III API is Metformin or a salt or solution thereof.

6. A pharmaceutical formulation as claimed in any of claims 1 to 5 wherein the ratio of agar to alginate is from 1 .6:1 to 5.6:1 .

7. A pharmaceutical formulation as claimed in claim 6 wherein the ratio of agar to alginate is from 2.4:1 to 5.2:1 .

8. A pharmaceutical formulation as claimed in claim 6 or 7 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.

9. A pharmaceutical formulation as claimed in claim 8 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.

10. A pharmaceutical formulation as claimed in any of claims 1 to 9 wherein iv) the cation donator is a divalent cation.11 . A pharmaceutical formulation as claimed in any of claims 10 wherein iv) the divalent cation is magnesium.

12. A pharmaceutical formulation as claimed in claim 10 or 11 wherein ratio of alginate to divalent cation, by weight %, is from 3:1 to 7:1 .

13. A pharmaceutical formulation as claimed in claim 12 wherein the divalent cation is present in an amount, by weight %, of from 0.01 to 0.07.

14. A pharmaceutical formulation as claimed in any of claims 1 to 13 wherein v) the preservative is potassium sorbate.

15. A pharmaceutical formulation as claimed in any of claims 2 to 14 wherein vii) the pH modifier is one of citric acid, sodium citrate, sodium bicarbonate or sodium hydroxide.

16. A pharmaceutical formulation as claimed in claim 15 wherein the pH is between 4.0 and 7.5.

17. A pharmaceutical formulation as claimed in any of claims 2 to 16 wherein viii) the solubiliser is glycerol.

18. A pharmaceutical formulation as claimed in any of claims 2 to 17 wherein viii) the thickening agent is xanthan gum.

19. A pharmaceutical formulation as claimed in any of claims 18 wherein the xanthan gum is present in an amount of from 0.1 to 0.4 % by wt.

20. A pharmaceutical formulation as claimed in any of claims 1 to 14 wherein the formulation comprises ingredients in the amounts (% by wt) as Table 23.21 . A pharmaceutical formulation as claimed in any of claims 2 to 19 wherein the formulation comprises ingredients in the amounts (% by wt) as Table 24.

22. A pharmaceutical formulation as claimed in claim 3 wherein i) the API is Cetirizine or a salt or solution thereof.

23. A pharmaceutical formulation as claimed in claim 22 wherein i) the salt is a hydrochloride.

24. A pharmaceutical formulation as claimed in claim 22 or 23 wherein the formulation comprises ingredients (by weight %) in the range as Table 1 aTable 1aor Table 14a.

25. A pharmaceutical formulation as claimed in claim 24 wherein the formulation comprises ingredients (by weight %) in the range as Table 1 bTable 1bor Table 14b26. A pharmaceutical formulation as claimed in claim 22, 23, 24 or 25 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 1cTable 1cor Table 14cor Table 14d27. A pharmaceutical formulation as claimed in claim 3 wherein i) the API is Doxycycline or a salt or solution thereof.

28. A pharmaceutical formulation as claimed in claim 27 wherein the formulation comprises ingredients (by weight %) in the range as Table 2a.Table 2a29. A pharmaceutical formulation as claimed in claim 26 or 27 wherein the formulation comprises ingredients (by weight %) in the range as Table 2b.Table 2b30. A pharmaceutical formulation as claimed in claim 27, 28 or 29 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 2c, Table 15a or 15b.Table 2cor Table 15aor Table 15b31 . A pharmaceutical formulation as claimed in claim 3 wherein the API is Levetiracetam or a salt or solution thereof.

32. A pharmaceutical formulation as claimed in claim 31 wherein the formulation comprises ingredients (by weight %) in the range as Table 3a.Table 3a33. A pharmaceutical formulation as claimed in claim 32 wherein the formulation comprises ingredients (by weight %) in the range as Table 3b.Table 3b34. A pharmaceutical formulation as claimed in claim 31 , 32 or 33 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 3c,Table 3cor Table 16aor Table 16b35. A pharmaceutical formulation as claimed in claim 3 wherein the API is Bupropion or a salt or solution thereof.

36. A pharmaceutical formulation as claimed in claim 35 wherein the formulation comprises ingredients (by weight %) in the range as Table 4a.Table 4a37. A pharmaceutical formulation as claimed in claim 36 wherein the formulation comprises ingredients (by weight %) in the range as Table 4b.Table 4b38. A pharmaceutical formulation as claimed in claim 35, 36 or 37 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 4cTable 4cor Table 17aor Table 17b39. A pharmaceutical formulation as claimed in claim 3 wherein the API is Venlafaxine or a salt or solution thereof.

40. A pharmaceutical formulation as claimed in claim 39 wherein the formulation comprises ingredients (by weight %) in the range as Table 5a.Table 5a41 . A pharmaceutical formulation as claimed in claim 40 wherein the formulation comprises ingredients (by weight %) in the range as Table 5b.Table 5b42. A pharmaceutical formulation as claimed in claim 39, 40 or 41 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 5cTable 5cor Table 18aor Table 18b43. A pharmaceutical formulation as claimed in claim 3 wherein the API is Paracetamol or a salt or solution thereof.

44. A pharmaceutical formulation as claimed in claim 43 wherein the formulation comprises ingredients (by weight %) in the range as Table 6a.Table 6a45. A pharmaceutical formulation as claimed in claim 44 wherein the formulation comprises ingredients (by weight %) in the range as Table 6b.Table 6b46. A pharmaceutical formulation as claimed in claim 43, 44 or 45 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 6cTable 6cor Table 19aor Table 19b47. A pharmaceutical formulation as claimed in claim 4 wherein the formulation comprises ingredients (by weight %) in the range as Table 20a.

48. A pharmaceutical formulation as claimed in claim 47 wherein the formulation comprises ingredients (by weight %) in the range as Table 20b.

49. A pharmaceutical formulation as claimed in claim 48 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 20cor Table 20d50. A pharmaceutical formulation as claimed in claim 4 wherein the formulation comprises ingredients (by weight %) in the range as Table 21 a.51 . A pharmaceutical formulation as claimed in claim 50 wherein the formulation comprises ingredients (by weight %) in the range as Table 21 b.

52. A pharmaceutical formulation as claimed in claim 51 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 21cor Table 21d53. A pharmaceutical formulation as claimed in claim 5 wherein the formulation comprises ingredients (by weight %) in the range as Table 22a.

54. A pharmaceutical formulation as claimed in claim 53 wherein the formulation comprises ingredients (by weight %) in the range as Table 22b.

55. A pharmaceutical formulation as claimed in claim 54 wherein the formulation comprises ingredients (by weight (g) or weight %) as set out in Table 22cor Table 22d

Images