Lipophilic drug suspensions

Abstract

Specific combinations of water soluble salts of arylalkanoic acids and glyceryl esters when mixed together in water form a 'liquid scaffold' structure that will reliably suspend significant quantities of lipophilic drugs.

Description

[0001] Lipophilic Drug Suspensions

[0002] Background of the invention

[0003] Lipophilic drugs comprise the largest quantity (approximately 70%) of commercially available drugs. The preferred dosage route for drugs is oral, and it therefore follows that most lipophilic drugs are desired to be prepared as a stable suspension of solid particles in water.

[0004] Fine milling, together with added viscosifiers / dispersing agents is a common solution, but this only allows a few percent of solids to be reliably suspended. CALPOL ® is a good example of this technique, CALPOL ® is essentially a milled dispersion of paracetamol plus polymer marketed as suitable for treating fever in infants. CALPOL ® only contains around 2.4% w / w of paracetamol, and is a viscous syrup. Attempts to produce much higher concentrations of paracetamol that are suitable for adults by this technique simply produces thick pastes that are not commercially viable. This is a significant reason why painkillers for adults are only available in tablet form.

[0005] Matching the density of the dispersed solid to that of the aqueous dispersing medium may produce a stable suspension. However, the matched densities will immediately diverge with any significant change in temperature and this will destabilise the system, resulting in a system which is not commercially viable.

[0006] Due to the aforementioned difficulties, many lipophilic drugs are therefore formulated by dissolving them in mixtures of ethanol plus water. However; this presents a problem for patients whose religious beliefs forbid the imbibing of intoxicating alcohol. These patients currently do not have an alternative for many commercial drugs.

[0007] There therefore remains a desperate need within the pharmaceutical industry for a stable, orally acceptable formulation that is capable of suspending significant (25% w / w for example) amounts of lipophilic drugs in water.

[0008] Summary of the invention

[0009] According to a first aspect of the invention, there is provided an oral suspension system comprising an aqueous solution of at least one glyceryl ester and at least one water-soluble salt of an arylalkanoic acid.

[0010] The oral suspension system may be for a lipophilic drug.

[0011] Advantageously, we recently made the surprising discovery that certain specific orally acceptable combinations of water soluble salts of arylalkanoic acids and glyceryl esters when mixed together in water will reliably suspend significant quantities of lipophilic drugs.

[0012] It is believed that the arylalkanoic acid salts combine with glyceryl esters to form a thermodynamically stable 3D matrix which can suspend lipophilic particles of solid (or liquid droplets) in water. The matrix immobilises the lipophilic particles (i.e., it prevents the particles from either settling downwards or floating upwards). The system will also dependably support bubbles of air shaken into the formulation; this is by itself indicative of very strong suspending power.

[0013] While the inventors do not wish to be bound by theory, it is presently understood that the mechanism by which lipophilic drugs are suspended in water by this particular combination of amphiphilic molecules (i.e., the glyceryl ester and the water-soluble salt of an arylalkanoic acid) involves the arylalkanoic acid salts and the glyceryl esters forming extremely tiny (smaller than the wavelength of visible light) regular sized hollow spheres. The spheres are thought to be constructed from L - alpha (liquid crystal) phase. The spheres are believed to be stabilised both on their internal and external surface by a combination of hydrogen bonding from the hydroxyl groups on the glyceryl ester and by resonance from the carboxyl group on the acid.

[0014] The hydrophilic portion of the acid molecules may be ionised in water, forming a regular sized micro sphere which is neutral overall but, due to ionisation, comprising a positive 'shell' that completely envelops a negative surface. The regular sized micro spheres may have equivalent surface charge so they repel each other with matching force and, if they are present in sufficient quantity, they arrange themselves into a 'liquid scaffold' structure that fills all the available space.

[0015] It is understood that each micro sphere in the liquid scaffold structure is continually repelling its neighbours, and is being pushed in return by them. Without wishing to be bound by theory, one can therefore envisage particles of solid, liquid, or gas that are introduced into the scaffold being continually pushed from all sides by the micro spheres and therefore held in suspension. This hypothesis is consistent with the observation that the yield point of the scaffold reduces with added electrolyte. Ions in solution in the spaces between the micro spheres may 'shield' the micro spheres from each other, reduce repulsion, and therefore reduce yield point.

[0016] Again, without wishing to be bound by theory, the extremely small size of the spheres can be gauged by the observation that the scaffold structure is essentially transparent to visible light. The spheres may therefore either be of the same refractive index as the continuous phase (this is thought to be unlikely), or be smaller than the light wavelength. When a test tube of the 'scaffold structure' is viewed between polarizing sheets a very weak birefringence is observed which is believed to be consistent with a structure of packed micro spheres constructed from L - alpha phase.

[0017] The glyceryl ester may be any glyceryl ester, for example the glyceryl ester may be a glyceryl caprate / caprylate. Advantageously, glyceryl caprate / caprylate has a low melting point (making it easy to use), and a pleasant odour.

[0018] The glyceryl ester may be a glyceryl ester from the group consisting of: Glyceryl Laurate, Glyceryl Laurate SE, Glyceryl Laurate / Oleate, Glyceryl Arachidate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate / Caprate, Glyceryl Cocoate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate, Glyceryl Isostearate / Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl Isotridecanoate / Stearate / Adipate, Glyceryl Oleate SE, Glyceryl Oleate / Elaidate, Glyceryl Palmitate, Glyceryl Palmitate / Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Rosinate, Glyceryl / Sorbitol Oleate / Hydroxystearate, Glyceryl Stearate / Malate, Glyceryl Tallowate, Glyceryl Undecylenate, and combinations thereof.

[0019] The glyceryl ester may be a glyceryl ester from the group consisting of: Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Collagenate, Glyceryl Laurate, Glyceryl Laurate / Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate / Caprate, Glyceryl Citrate / Lactate / Linoleate / Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate. Glyceryl Isostearate / Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl Isotridecanoate / Stearate / Adipate, Glyceryl Oleate / Elaidate, Glyceryl Palmitate, Glyceryl Palmitate / Stearate, Glyceryl Palmitoleate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryl / Sorbitol Oleate / Hydroxystearate, Glyceryl Stearate / Acetate, Glyceryl Stearate / Malate, Glyceryl Tallowate, Glyceryl Thiopropionate, Glyceryl Undecylenate, and combinations thereof.

[0020] The glyceryl ester may be any C4, C5, C6, C7, C8, C9, CIO, Cll, C12, C13 or C14 glyceryl ester. In preferred embodiments, the glyceryl ester may be a C8, C9 or CIO glyceryl ester.

[0021] The arylalkanoic acid may be any C4, C5, C6, C7, C8, C9, CIO, Cll, C12, C13 or C14 arylalkanoic acid.

[0022] While they may be used in the invention, glyceryl esters with shorter chains (for example less than C8) have decreasing lipophilic character and are less likely to combine with the acid salts to form L- alpha phase. They are also more volatile and have stronger odours. Nevertheless, such shorter-chain glyceryl esters may be combined with additives in the oral suspension system to ameliorate such disadvantages.

[0023] The water-soluble salt of an arylalkanoic acid may comprise any water-soluble salt of an arylalkanoic acid, or combinations of water-soluble salts of arylalkanoic acids, which belong to the specific group of pharmaceutical drugs known as the NSAID's (non-steroidal anti-inflammatory drugs). For example, the water-soluble salt of an arylalkanoic acid may be selected from the group consisting of: ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, aspirin, and combinations thereof.

[0024] The water-soluble salt of an arylalkanoic acid may comprise a water-soluble salt of cinnamic acid. Cinnamic acid may be present in combination with any one or more of the aforementioned pharmaceutical drugs known as the NSAID's.

[0025] In embodiments comprising a water-soluble salt of cinnamic acid, the cation of the water-soluble salt of cinnamic acid may comprise singly or a mixture of sodium and / or potassium.

[0026] In preferred embodiments, the water-soluble salt of arylalkanoic acids may be a water-soluble salt of Ibuprofen. In such embodiments, the cation of the water-soluble salts of Ibuprofen may comprise singly or a mixture of sodium and / or potassium.

[0027] In some embodiments, the water-soluble salt of arylalkanoic acids may be a water-soluble salt of Mefenamic acid, for example the water-soluble sodium salt of Mefenamic acid, i.e., sodium mefenamate.

[0028] In some embodiments, the water-soluble salt of arylalkanoic acids may be a water-soluble salt of tolmetin, for example the water-soluble sodium salt of tolmetin, i.e., sodium tolmetin.

[0029] The w / w ratio of the water-soluble salt of an arylalkanoic acid to the glyceryl ester may be in the range of from about 1:2.5 to about 1.00:3.50, for example from about 1.00:2.60 to about 1.00:3.40, from about 1.00:2.75 to about 1.00:3.25, from about 1.00:2.80 to about 1.00:3.20, from about 1.00:2.90 to about 1.00:3.10, for example from about 1.00:3.0.

[0030] The w / w ratio of the water-soluble salt of an arylalkanoic acid to the glyceryl ester may be in the range of from about 1.00:3.00 to about 1.00:7.00, for example from about 1.00:4.00 to about 1.00:7.00, from about 1.00:5.00 to about 1.00:7.00, from about 1.00:5.50 to about 1.00:6.50, or about 1.00:6.00.

[0031] In some embodiments, the water-soluble salt of an arylalkanoic acid may be a water-soluble salt of Ibuprofen and the glyceryl ester may be glyceryl caprate / caprylate. In such an embodiment, the water-soluble salt of Ibuprofen may be a water-soluble sodium salt of Ibuprofen, for example sodium ibuprofen dihydrate. In such an embodiment, the w / w ratio of sodium ibuprofen dihydrate to glyceryl caprate / caprylate may be within the range of from about 1.00:2.50 to about 1.00:3.50, for example from about 1.00:2.60 to about 1.00:3.40, from about 1.00:2.75 to about 1.00:3.25, from about 1.00:2.80 to about 1.00:3.20, from about 1.00:2.90 to about 1.00:3.10, for example about 1.00:3.0.

[0032] In some embodiments, the water-soluble salt of Ibuprofen may be a water-soluble potassium salt of Ibuprofen, for example potassium ibuprofen. In such an embodiment, the glyceryl ester may be glyceryl caprate / caprylate. In such an embodiment, the w / w ratio of potassium ibuprofen to glyceryl caprate / caprylate may be within the range from about 1.00:3.00 to about 1.00:7.00. For example, from about 1.00:5.00 to about 1.00:7.00, from about 1.00:5.50 to about 1.00:6.50, for example about 1.00:6.00.

[0033] The total amount of active material (i.e., the water-soluble salt of an arylalkanoic acid plus the glyceryl ester) may comprise at least about 5% w / w of the total amount of water plus actives, for example at least about 10 % w / w, at least about 15% w / w, at least about 20% w / w, at least about 25% w / w, at least about 30% w / w, at least about 35% w / w, at least about 40% w / w, at least about 45% w / w, or at least about 50% w / w.

[0034] The total amount of active material (i.e., the water-soluble salt of an arylalkanoic acid plus the glyceryl ester) may comprise about 5% w / w of the total amount of water plus actives, for example about 10 % w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or about 50% w / w.

[0035] The total amount of active material (i.e., the water-soluble salt of an arylalkanoic acid plus the glyceryl ester) may comprise no more than about 5% w / w of the total amount of water plus actives, for example about 10 % w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or no more than about 50% w / w.

[0036] The oral suspension system may further comprise one or more lipophilic drugs. The one or more lipophilic drugs may be dispersed within the oral suspension system. The oral suspension system may be a stable suspension.

[0037] The oral suspension system may comprise one or more lipophilic drugs in an amount of at least about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or at least about 50% by weight, of the total system.

[0038] The oral suspension system may comprise one or more lipophilic drugs in an amount of about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight, of the total system.

[0039] The oral suspension system may comprise one or more lipophilic drugs in an amount of no more than about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or no more than about 50% by weight, of the total system.

[0040] The oral suspension system may comprise one or more compounds selected from the group comprising at least: sweetening agent, preservative, colourant and flavouring, and combinations thereof. Beneficially, each of these compounds may provide a more palatable commercial formulation.

[0041] According to a further aspect of the invention, there is provided a binary blend of a glyceryl ester and a water-soluble salt of at least one arylalkanoic acid. The glyceryl ester may be any glyceryl ester disclosed in relation to the first aspect of the invention. The water-soluble salt of at least one arylalkanoic acid may be a water-soluble salt of any arylalkanoic acid disclosed in relation to the first aspect of the invention.

[0042] In some embodiments, the glyceryl ester may be glyceryl caprate / caprylate. In some embodiments, the water-soluble salt of at least one arylalkanoic acid may be the sodium salt of ibuprofen.

[0043] In an embodiment, the blend may be a thin isotropic liquid at room temperature. In an embodiment comprising glyceryl caprate / caprylate and the sodium salt of ibuprofen, the w / w ratio of the sodium salt of ibuprofen to glyceryl caprate / caprylate may be within the range of from about 1.00:2.50 to about 1.00:3.50, for example from about 1.00:2.60 to about 1.00:3.40, from about 1.00:2.75 to about 1.00:3.25, from about 1.00:2.80 to about 1.00:3.20, from about 1.00:2.90 to about 1.00:3.10, for example about 1.00:3.0.

[0044] According to a further aspect of the invention, there is provided a ternary blend of a glyceryl ester and a water-soluble salt of at least one arylalkanoic acid. The glyceryl ester may be any glyceryl ester disclosed in relation to the first aspect of the invention. The water-soluble salt of at least one arylalkanoic acid may be a water-soluble salt of any arylalkanoic acid disclosed in relation to the first aspect of the invention.

[0045] In some embodiments, the glyceryl ester may be glyceryl caprate / caprylate. In some embodiments, the water-soluble salt of at least one arylalkanoic acid may be the potassium salt of ibuprofen.

[0046] The ternary blend may comprise up to about 10% w / w water, for example no more than about 1% w / w water, about 2% w / w water, about 3% w / w water, about 4% w / w water, about 5% w / w water, about 6% w / w water, about 7% w / w water, about 8% w / w water, about 9% w / w water, or no more than about 10% w / w water.

[0047] The ternary blend may comprise up to about 10% w / w water, for example about 1% w / w water, about 2% w / w water, about 3% w / w water, about 4% w / w water, about 5% w / w water, about 6% w / w water, about 7% w / w water, about 8% w / w water, about 9% w / w water, or about 10% w / w water.

[0048] In an embodiment, the blend may be a thin isotropic (reverse micellar) liquid at room temperature.

[0049] In an embodiment comprising glyceryl caprate / caprylate and potassium ibuprofen, the w / w ratio of potassium ibuprofen to glyceryl caprate / caprylate may be within the range from about 1.00:3.00 to about 1.00:7.00. For example, from about 1.00:5.00 to about 1.00:7.00, from about 1.00:5.50 to about 1.00:6.50, for example about 1.00:6.00.

[0050] It will be understood that each aspect of the invention may comprise any feature, optional or otherwise, of any other aspect of the invention. Detailed description of an embodiment of the invention

[0051] In an example embodiment of the invention, there is provided a suspending system constructed from mixtures of water soluble salts of arylalkanoic acids and glyceryl esters in water which will be described as follows.

[0052] Arylalkanoic acids that are of explicit interest to this invention belong to the group of pharmaceutical drugs known as the NSAID's (non-steroidal anti-inflammatory drugs).

[0053] The specific NSAID's that may form the liquid scaffold structure in combination with glyceryl esters are those ones that possess water soluble salts. And of these we have targeted the molecules that have already been licenced for oral ingestion. Although, we would also wish to claim those water soluble salts of NSAID's that are not currently approved, but could potentially attain approval given sufficient commercial interest.

[0054] The NSAID's with water soluble salts that we have found to form the scaffold structure in combination with glyceryl esters are listed in Figure 1.

[0055] Figure 1 shows NSAID's with water soluble salts that we have found to form the scaffold structure in combination with glyceryl esters

[0056] As an example of the invention, the orally approved glyceryl ester that finds particular benefit in constructing the liquid scaffold is glyceryl caprate / caprylate. This is in part due to its low melting point (making it easy to use), and its pleasant odour. Although; it should be apparent that other glyceryl esters which have differing alkyl chain distributions might also give useful suspending scaffolds.

[0057] An embodiment of the invention comprising glyceryl caprate / caprylate (mixed C8 / C10 carbon chains) and sodium ibuprofen as the water-soluble salt of an arylalkanoic acid is described herein.

[0058] Further examples described comprise sodium naproxen powder and potassium cinnamate powder.

[0059] The ibuprofen powder used experimentally was standard pharmaceutical grade material of Chinese manufacture.

[0060] The sodium ibuprofen that was used was a commercially available sodium ibuprofen dihydrate grade supplied by BASF.

[0061] The sodium naproxen powder used was standard pharmaceutical grade material of Chinese manufacture.

[0062] The potassium cinnamate powder used was standard food grade material of Chinese manufacture.

[0063] The glyceryl ester was a commercially available glyceryl caprate / caprylate (99% glycerides) supplied by STEPAN Co, trade name STEPAN MILD GCC.

[0064] Several sodium ibuprofen dihydrate / glyceryl caprate / caprylate mixtures were dispersed in warm (40 Degrees C.) water by charging all components then agitating gently by hand with a metal spatula for several minutes. The total concentration of ibuprofen plus glyceryl caprate / caprylate was fixed at 15% w / w. The ratio of ibuprofen to ester was varied over the range from 1.00:2.00 to 1.00:4.00 w / w.

[0065] Suspending matrices were observed over the entire range from 1.00:2.50 to 1.00:3.50 w / w. The matrix strength (suspending power) of each sample was estimated from viscosity and the bubble sizes of any naturally entrained air. Thicker samples with larger bubbles having the best suspending power. It was observed that the strongest matrix was 1.00:3.00 w / w sodium ibuprofen dihydrate: glyceryl caprate / caprylate.

[0066] Several sodium naproxen / ester mixtures were dispersed in warm (50 Degrees C.) water by charging all components then agitating gently by hand with a metal spatula for several minutes. The total concentration of sodium naproxen plus glyceryl caprate / caprylate was fixed at 15% w / w. The ratio of sodium naproxen to glyceryl caprate / caprylate was varied over the range from 1.00:2.00 to 1.00:6.00 w / w.

[0067] Suspending matrices were observed over the range from 1.00:3.00 to 1.00:5.00 w / w. The matrix strength (suspending power) of each sample was estimated from viscosity and the bubble sizes of any naturally entrained air. Thicker samples with larger bubbles having the best suspending power. It was observed that the strongest matrix was 1.00:3.75 w / w sodium naproxen: glyceryl caprate / caprylate. All the suspending matrices were observed behind sheets of Polaroid film; a weak 'shimmering' upon agitating the samples indicated a liquid crystal structure.

[0068] Upon storage after several days at room temperature, it has been observed that a small number of naproxen derived suspending matrices samples over the range from 1:3 to 1:5 w / w collapsed to yield an oily surface layer over a cloudy aqueous. It is believed that prior to storage for several days, a metastable drug suspension was formed. However, without wishing to be bound by theory, it is believed that a methoxy group on the naproxen molecule is the cause of the instability by producing the metastable matrix. This metastable drug suspension could potentially have applications to produce suspensions for immediate consumption, e.g. in hospitals and nursing homes.

[0069] Samples were prepared at 1.00:3.00 w / w sodium ibuprofen dihydrate: ester from 10% to 20% w / w total actives. Suspending power increased gradually from thin watery with tiny bubbles at 10% to very thick with large bubbles at 20%. Several potassium ibuprofen / ester mixtures were prepared by charging ibuprofen, potassium hydroxide, glyceryl ester, and warm water then agitating gently by hand with a metal spatula for several minutes. The total concentration of potassium ibuprofen plus ester was fixed at 15% w / w. The ratio of potassium ibuprofen to ester was varied over the range from 1:2 to 1:7 w / w.

[0070] Suspending matrices were observed over the range from 1.00:3.00 to 1.00:7.00 w / w. The matrix strength (suspending power) of each sample was estimated from viscosity and the bubble sizes of any naturally entrained air. Thicker samples with larger bubbles having the best suspending power. It was observed that samples with both a high degree of clarity and high yield point were obtained over the range 1.00:5.00 to 1.00:7.00 w / w potassium ibuprofen: ester.

[0071] A mixed sodium naproxen / sodium ibuprofen / glyceryl caprate / caprylate system was prepared using the previously discovered 'optimum structuring ratio' for each salt (i.e. 3.75:1.00 w / w for naproxen and 3.00:1.00 w / w for ibuprofen). 85g of hot (60 Deg.C.) water was mixed with 11.55g of glyceryl caprate / caprylate, 1.87g sodium ibuprofen dihydrate and 1.58g of sodium naproxen. The sample had high clarity and a strong yield point (as evidenced by it suspending large bubbles). This demonstrates intermix ability of ibuprofen and naproxen suspending systems and suggests that they have a comparable physical structure.

[0072] However, the mixed sodium naproxen / sodium ibuprofen / glyceryl caprate / caprylate system described above proved to be metastable and separated after several days at room temperature. It is believed (as previously discussed) that the methoxy group on the naproxen molecule is the cause of the instability. A w / w blend of 1 part potassium ibuprofen to 6 parts glyceryl caprate / caprylate was prepared by adding 25% aqueous KOH to a mixture of ibuprofen and glyceryl ester. A thin, isotropic reverse micellar phase containing 8.8% water was obtained which provides a practical feedstock for use in formulating drug dispersions.

[0073] Sodium ibuprofen dihydrate is a powder at room temperature and glyceryl caprate / caprylate is a waxy solid. It was found that if a 1.00:3.00 w / w blend of ibuprofen: ester was warmed and stirred at ca. 50 Degrees C. a thin isotropic liquid was obtained which remained unchanged on cooling naturally to room temperature. This result was unexpected, but nevertheless provides a practical blend for use in formulating drug dispersions.

[0074] The liquid 1.00:3.00 w / w blend of sodium ibuprofen dihydrate: glyceryl caprate / caprylate was mixed into water at room temperature in the ratio of 15:85 w / w. The sample obtained was physically identical to that obtained by mixing all components separately. Several portions of crystalline sucrose were added incrementally up to 20% w / w with stirring to the sample. The sucrose dissolved readily without affecting suspending power, i.e. no change in physical appearance was observed.

[0075] 20 grams of Ibuprofen powder was slurried with 68 grams of water. 12 grams of the liquid 1.00:3.00 w / w blend of ibuprofen: ester was then stirred in until the mixture thickened. The resultant sample was pourable and of a viscosity such that it sat in a 5ml dosing spoon with a proud meniscus. It suspended entrained air bubbles and showed no separation of suspended ibuprofen crystals after 6 months at room temperature.

[0076] It was speculated that the 'simple amphiphile' sodium benzoate might have sufficient lipophilic character to combine with glyceryl caprate / caprylate in the same manner as (for example) sodium ibuprofen. It was deemed important to test the hypothesis since sodium benzoate is an approved excipient for oral pharmaceuticals.

[0077] Various w / w ratios of sodium benzoate: glyceryl caprate / caprylate were examined and little evidence was found of any suspending matrix. This demonstrates that a single benzyl group may have insufficient lipophilic character.

[0078] A molecule with a greater degree of lipophilic character than sodium benzoate (but less than sodium ibuprofen) is potassium cinnamate. It is approved for use in foods but not in medicines. It was thought that structure formation when combined with glyceryl caprate / caprylate would indicate a 'lower limit' and consequently it was considered important to test it.

[0079] A series of samples were prepared containing 15% w / w total amphiphile in water over the range 1.00:1.00 to 1.00:7.00 w / w potassium cinnamate: glyceryl caprate / caprylate. Weakly structured liquids (as evidenced by the suspension of tiny air bubbles) were observed at two ratios; these were 1.00:1.50 and 1.00:2.00.

[0080] A further sample was then prepared containing 20% w / w total amphiphile in water at a ratio of 1.00:1.75. This sample had a high degree of clarity, a viscosity of ca. 800cps, and had excellent suspending power (as evidenced by the suspension of large air bubbles).

[0081] These results show that cinnamate does combine with glyceryl caprate / caprylate ester in a like manner to ibuprofen, and exhibit comparable suspending power. Greater suspending power of a system comprising potassium cinnamate and glyceryl caprate / caprylate may be achieved by increasing the total active concentration.

[0082] From foregoing results a simple empirically derived approximation may therefore be written: %A. + %B > 8% (by weight) of the final pharmaceutical formulation where:

[0083] A = water soluble salt(s) of arylalkanoic acid(s) with 8 - 14 carbon atoms in the molecule

[0084] B = glyceryl ester(s) with 8 - 10 carbon atoms in the hydrophobic tail(s)

[0085] Examples

[0086] The following examples describe some of the embodiments of the invention without limiting the technology thereto.

[0087] Example 1 20% paracetamol suspension

[0088] A 'paracetamol powder' was prepared by crushing commercial 500 mg paracetamol tablets in a pestle and mortar. 13.8 grams of this powder was mixed together (by hand at room temperature) with 53.12 grams of a 12.5% w / w aqueous dispersion of a 3.00:1.00 w / w blend of Stepan Mild glyceryl caprate / caprylate: sodium ibuprofen dihydrate. The resultant suspension was a homogeneous low viscosity (around 550 cp) opaque white liquid. It showed no separation or sedimentation after storing at room temperature for 6 months.

[0089] Example 2 structuring blend

[0090] 300 grams of Stepan-Mild glyceryl caprate / caprylate was stirred together at 60 Degrees Centigrade with 100 grams of sodium ibuprofen dihydrate until a clear low viscosity solution was obtained. The solution remained clear and thin upon cooling to room temperature.

[0091] Example 3 25% ibuprofen suspension - sodium salt

[0092] 25 grams of Ibuprofen powder was slurried in 66 grams of water at room temperature. 9 grams of the blend prepared in Example 2 was added to the slurry and stirred until the viscosity began to increase. The resultant suspension was a homogeneous low viscosity (around 1000 cp) opaque white liquid. It showed no separation or sedimentation after storing at room temperature for 6 months.

[0093] Example 4 25% ibuprofen suspension - potassium salt

[0094] 26.9g of ibuprofen powder was slurried in 62.04g of water at ca. 40 Deg.C. 9.0g of Stepan Mild glyceryl caprate / caprylate and 2.06g of 25% w / w aqueous KOH solution was charged to the slurry and stirred manually until the viscosity began to increase. The resultant suspension was a homogeneous low viscosity (around 2500 cp) opaque white liquid. It showed no separation or sedimentation after storing at room temperature for 6 months.

[0095] Example 5 sweetened 25% ibuprofen suspension

[0096] 25 grams of Ibuprofen powder was slurried in 66 grams of a 30% w / w sucrose solution. 9 grams of the blend prepared in Example 2 was added to the slurry and stirred until the viscosity began to increase. The resultant suspension was a homogeneous low viscosity (around 1500 cp) opaque white liquid. It showed no separation or sedimentation after storing at room temperature for 6 months.

[0097] Example 6 25% paracetamol suspension

[0098] 16.83 grams of the 'paracetamol powder' prepared in Example 1 was slurried in 44.44 grams of water at room temperature. 6.05 grams of the blend prepared in Example 2 was added to the slurry and stirred until the viscosity began to increase. The resultant suspension was a homogeneous low viscosity (around 700 cp) opaque white liquid. It showed no separation or sedimentation after storing at room temperature for 6 months.

[0099] Example 7 sweetened suspending matrix

[0100] 1.8g of 25% aqueous KOH was added to a mixture of 1.8g of ibuprofen, 12.8g of Stepan Mild glyceryl caprate / caprylate and 83.4g of 25% aqueous sucrose solution. The resultant sample was transparent with a viscosity of ca. 1500 cp and strong suspending power as evidenced by suspended entrained air bubbles.

[0101] Example 8 sweetened / flavoured suspending matrix

[0102] 63.29g of warm (40 Deg.C.) water was added to a mixture of 2.11g ibuprofen, 12.5g of Stepan Mild glyceryl caprate / caprylate, and 20.0g of sucrose and stirred by hand until all the glyceryl caprate / caprylate had melted. 2.1g of 25% aqueous KOH was added and stirred by hand until the sample cleared and thickened. 1.0g of concentrated water soluble 'strawberry food flavouring' and 0.24g of sucralose was then mixed in. The resultant sample was transparent with a viscosity of ca. 3000 cp and a c. pH of 8.0. It had strong suspending power as evidenced by suspended entrained air bubbles.

[0103] Example 9 suspending power

[0104] A liquid 1.00:3.00 w / w blend of sodium ibuprofen dihydrate: glyceryl caprate / caprylate was mixed into water at room temperature in the ratio of 15:85 w / w. The sample obtained was physically identical to that obtained by mixing all components separately. The sample was poured into a glass test tube. Several plastic (toy) 7mm dice were then pushed into the centre of the tube. The dice had previously been added to a test tube containing water and immediately sank to the bottom of the tube. The dice remained where they were pushed and showed no settlement / movement after 6 months storage at room temperature as evidenced by several photographs taken during storage.

Claims

Claims1. An oral suspension system for lipophilic drugs that is formulated from blends of glyceryl ester and the water soluble salts of arylalkanoic acids in water2. The system of claim 1 wherein the glyceryl ester is a glyceryl caprate / caprylate3. The system of claim 2 wherein the water soluble salts of arylalkanoic acids belong to the specific group of pharmaceutical drugs known as the NSAID's (non-steroidal anti-inflammatory drugs)3.1 The system of claim 2 wherein the water soluble salts of arylalkanoic acids are those of cinnamic acid3.2 The system of claim 3.1 wherein the cation of the water soluble salts of cinnamic acid may comprise singly or a mixture of sodium and potassium4. The system of claim 3 wherein the NSAID is Ibuprofen5. The system of claim 4 wherein the cation of the water soluble salts of Ibuprofen may comprise singly or a mixture of sodium and potassium6. The system of claim 5 wherein the w / w ratio of sodium ibuprofen dihydrate to glyceryl caprate / caprylate lies inside the range from 1:2.5 to 1:3.

5. Preferably from 1:2.75 to 1:3.25, most preferably 1:2.9: 1:3.1, ideally 1:3.

07. The system of claim 5 wherein the w / w ratio of potassium ibuprofen to glyceryl caprate / caprylate lies inside the range from 1:3 to 1:

7. Preferably from l:5to 1:7, most preferably 1:5.5 1:6.5, ideally 1:6.

08. A system of claims 6 and / or 7 wherein the total amount of active material (sodium and / or potassium ibuprofen plus glyceryl caprate / caprylate) comprises at least 10% w / w of the total amount of water plus actives9. A system of claim 8 to which a significant quantity of lipophilic drug (or drugs) has been added and mixed in to give a stable suspension, wherein the amount of lipophilic drug (or drugs) is at least 5% by weight of the completed formulation, more usually at least 10%, typically at least 15%, ideally at least 20%10. A system of claim 9 to which sweetening agents, preservatives, colourants and flavours have been added in order to construct a palatable commercial formulation10. A simple binary blend of glyceryl caprate / caprylate and the sodium salt of ibuprofen, wherein the blend is a thin isotropic liquid at room temperature and the w / w ratio of sodium ibuprofen to glyceryl caprate / caprylate lies inside the range from 1:2.5 to 1:3.

5. Preferably from 1:2.75 to 1:3.25, most preferably 1:2.9: 1:3.1, ideally 1:3.

011. A ternary blend of glyceryl caprate / caprylate, the potassium salt of ibuprofen, and up to 10% water. Wherein the blend is a thin isotropic (reverse micellar) liquid at room temperature and the w / w ratio of potassium ibuprofen to glyceryl caprate / caprylate lies inside the range from 1:3 to 1:

7. Preferably from 1:5 to 1:7, most preferably 1:5.5 1:6.5, ideally 1:6.0.

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