WO2005007133A1 - Structured surfactant systems - Google Patents
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- WO2005007133A1 WO2005007133A1 PCT/GB2004/003051 GB2004003051W WO2005007133A1 WO 2005007133 A1 WO2005007133 A1 WO 2005007133A1 GB 2004003051 W GB2004003051 W GB 2004003051W WO 2005007133 A1 WO2005007133 A1 WO 2005007133A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Definitions
- the invention relates to structured surfactant systems and to suspensions of water- insoluble, or sparingly soluble, particles therein.
- it relates to structured systems based on non-ionic and/or zwitterionic surfactants, suitable for applications in which high levels of anionic surfactant are unacceptable.
- the invention is especially relevant to pharmaceutical and veterinary suspensions, and in particular to aqueous structured surfactant systems capable of suspending water-insoluble pharmaceutical and veterinary active materials for internal use. It is generally suitable for preparations intended for oral administration. Certain compositions according to the invention could also be administered parenterally.
- the invention is also especially relevant to food and beverages which comprise a continuous liquid phase with suspended solids
- the invention is also especially useful for preparing a variety of industrial suspensions, where high levels of anionic surfactant are undesirable, such as calcium stearate for the cement and paper industries.
- the invention is also relevant generally to the suspension of solids or water-immiscible liquids in aqueous, structured-liquid surfactants, for example in cleaning preparations, personal care formulations, agricultural or horticultural applications.
- suspensions could only be made available as suspensions.
- medicinal suspensions undergo sedimentation on standing, leading to a risk of under or overdosing, if instructions to shake the bottle thoroughly are not fully complied with.
- a further problem is that only relatively low concentrations of solids can be suspended, without the product becoming unacceptably viscous. For these reasons the use of suspensions has largely been confined to paediatric medicine. Thus for example suspensions of paracetamol are widely used for treating infants, but no adult equivalent is available.
- Sedimentation is also a problem in a variety of food and drink products, including fruit squashes, pulps, purees, preserves and canned fruit and vegetables.
- Calcium stearate dispersions have been widely used, for many years, especially in the construction industry, as an additive to cement, to make the set product more water repellent, and also in the paper industry, to provide water repellent coatings to paper. They are also used as lubricants for abrasive coatings. Two long standing problems with such dispersions have been poor physical stability, leading to separation of the solids, and the adverse effect, from the point of view of the end user, of the surfactants, and especially the anionic surfactants, used to improve their stability. Such surfactants have been used as dispersatits, to render the particles more hydrophilic, by coating them with a monolayer of surfactant.
- Gums and polymeric thickeners which increase the viscosity of the liquid medium, retard, but do not prevent sedimentation, and at the same time make the composition harder to pour. They do not provide stable suspensions.
- the paediatric suspensions of paracetamol although fairly viscous, are not fully stable
- Colloidal dispersions contain particles of about 1 micron or smaller, which are prevented from sedimenting by Brownian motion.
- problems in preventing the agglomeration, or crystal growth of colloidal particles Most colloidal suspensions lack long term stability due to Ostwald ripening. For example attempts to provide stable colloidal suspensions of elemental selenium, to remedy dietary deficiencies in grazing animals, have proved unsuccessful.
- colloidal particles tend to dissolve rapidly, releasing the active ingredient within a short period after ingestion, whereas for most treatment regimes a slower, more controlled release is desirable.
- Structured suspending systems depend on the rheological properties of the suspending medium to immobilise the particles, irrespective of size. This requires the suspending medium to exhibit a yield point, which is higher than the sedimenting or creaming force exerted by the suspended particles, but low enough to enable the medium to flow under externally imposed stresses, such as pouring and stirring, like a normal liquid. The structure reforms sufficiently rapidly to prevent sedimentation, once the agitation caused by the external stress has ceased.
- structured system means a pourable composition comprising water, surfactant, any structurants, which may be required to impart suspending properties to the surfactant, and optionally other dissolved matter, which together form a mesophase, or a dispersion of a mesophase in a continuous aqueous medium, and which has the ability to immobilise non-colloidal, water- insoluble particles, while the system is at rest, thereby forming a stable, pourable suspension.
- L ⁇ -phases in which bilayers of surfactant are arranged with the hydrophobic part of the molecule on the interior and the hydrophilic part on the exterior of the bilayer (or vice versa).
- the bilayers lie side by side, e.g. in a parallel or concentric configuration, sometimes separated by aqueous layers.
- L ⁇ -phases also known as G- phases
- Such evidence may comprise first, second and sometimes third order peaks with a d- spacing (2 ⁇ /Q, where Q is the momentum transfer vector) in a simple integral ratio 1:2:3.
- Other types of symmetry give different ratios, usually non-integral.
- the d-spacing of the first peak in the series corresponds to the repeat spacing of the bilayer system.
- Dispersed lamellar phases are two phase systems in which the surfactant bilayers are arranged as parallel plates to form domains of L ⁇ -phase, which are interspersed with an aqueous phase to form an opaque gel-like system. They are described in EP 0086 614.
- Spherulitic phases comprise well-defined spheroidal bodies, usually referred to in the art as spherulites, in which surfactant bilayers are arranged as concentric shells.
- the spherulites usually have a diameter in the range 0.1 to 15 microns and are dispersed in an aqueous phase in the manner of a classical emulsion, but interacting to form a structured system.
- Spherulitic systems are described in more detail in EP 0 151 884. Many structured systems are intermediate between dispersed lamellar and spherulitic, involving both types of structure. Usually systems having a more spherulitic character are preferred because they tend to have lower viscosity.
- a variant on the spherulitic system comprises prolate or rod shaped bodies sometimes referred to as batonettes. These are normally too viscous to be of practical interest.
- Both of the foregoing systems comprise two phases. Their stability depends on the presence of sufficient dispersed phase to pack the system so that the interaction between the spherulites or other dispersed mesophase domains prevents separation. If the amount of dispersed phase is insufficient, e.g. because there is not enough surfactant or because the surfactant is too soluble in the aqueous phase to form sufficient of a mesophase, the system will undergo separation and cannot be used to suspend solids. Such unstable systems are not "structured" for the purpose of this specification.
- a third type of structured system comprises an expanded L ⁇ -phase. It differs from the other two types of structured system in being essentially a single phase, and from conventional L ⁇ -phase in having a wider d-spacing.
- Conventional L ⁇ -phases which typically contain 60 to 75% by weight surfactant, have a d-spacing of about 4 to 7 nanometers. Attempts to suspend solids in such phases result in stiff pastes which are either non-pourable, unstable or both.
- the H-phase comprises surfactant molecules arranged to form cylindrical rods of indefinite length. It exhibits hexagonal symmetry and a distinctive texture under the polarising microscope. Typical H-phases have so high a viscosity that they appear to be curdy solids. H-phases near the lower concentration limit (the L ⁇ -phase boundary) may be pourable but have a very high viscosity and often a mucous-like appearance. Such systems tend to form expanded L ⁇ -phases particularly readily on addition of sufficient electrolyte.
- Expanded L ⁇ -phases are described in more detail in EP 0530708. In the absence of suspended matter they are generally translucent, unlike dispersed lamellar or spherulitic phases which are normally opaque. They are optically anisotropic and have shear- dependent viscosity. In this they differ from Li -phases, which are micellar solutions or microemulsions. Li -phases are clear, optically isotropic and are usually substantially Newtonian. They are unstructured and cannot suspend solids.
- Li -phases exhibit small angle x-ray diffraction spectra which show evidence of hexagonal symmetry and/or exhibit shear dependent viscosity.
- Such phases usually have concentrations near the Li/H-phase boundary and may form expanded L ⁇ -phases on addition of electrolyte.
- electrolyte In the absence of any such addition of electrolyte they lack the yield point required to provide suspending properties, and are not, therefore, "structured systems" for the purpose of this specification.
- Expanded L ⁇ -phases of the above type are usually less robust than spherulitic systems. They are liable to become unstable at low temperatures. Moreover they frequently exhibit a relatively low yield stress, which may limit the maximum size of particle that can be stably suspended.
- structured surfactants require the presence of a structurant, as well as surfactant and water in order to form structured systems capable of suspending solids.
- the term "structurant” is used herein to describe any non-surfactant capable, when dissolved in water, of interacting with surfactant to form or enhance a structured system. It is typically a surfactant-desolubiliser, e.g. an electrolyte.
- certain relatively hydrophobic surfactants such as isopropylamine alkyl benzene sulphonate can form spherulites in water in the absence of electrolyte.
- Such surfactants are capable of suspending solids in the absence of any structurant, as described in EP 0414 549. Isopropylamine alkyl benzene sulphonate is not, however, a pharmacologically acceptable surfactant.
- a problem with the two phase, especially spherulitic, systems is flocculation of the dispersed surfactant structures. This tends to occur at high surfactant and or high electrolyte concentration. It can have the effect of making the composition very viscous and/or unstable with the dispersed surfactant separating from the aqueous phase.
- Certain amphiphilic polymers have been found to act as deflocculants of structured surfactants.
- One type of deflocculant polymer exhibits cteniform (comb-shaped) architecture with a hydrophilic backbone and hydrophobic side chains or vice versa.
- a typical example is a random copolymer of acrylic acid and a fatty alkyl acrylate.
- Cteniform deflocculants have been described in a large number of patents, for example WO-A-9106622.
- a more effective type of deflocculant has surfactant (linear) rather than cteniform architecture, with a hydrophilic polymer group attached at one end to a hydrophobic group.
- Such deflocculants are typically telomers formed by telomerising a hydrophilic monomer with a hydrophobic telogen.
- Examples of surfactant deflocculants include alkyl thiol p olyacrylates and alkyl p olyglycosides. S urfactant d eflocculants a re d escribed i n more detail in EP 0623 670.
- WO 01/00788 describes the use of carbohydrates such as sugars and alginates as deflocculants in structured surfactant compositions.
- the latter comprise surfactant, water and electrolyte in proportions adapted to form flocculated two-phase structured surfactant systems in the absence of the carbohydrate.
- deflocculant polymers can give rise to syneresis.
- the spherulitic suspending medium shrinks in volume leaving a clear portion of the continuous phase external to the spherulitic suspending medium.
- aqueous, structured systems in which the surfactant is normally less dense than the aqueous phase, this usually manifests itself as a clear lower layer ("bottom separation").
- auxiliary stabilisers have been suggested to inhibit or prevent syneresis or bottom separation of structured surfactant.
- US 5 602 092 has proposed the use of highly cross linked polyacrylates
- WO 01/00779 describes the use as auxiliary stabiliser of non-cross linked polymers with a hydrophilic back bone and sufficient short (e.g. C 1-5 ) hydrocarbon side chains to enhance physical entanglement of the polymer molecules, e.g. polymers of acrylic acid with ethyl acrylate.
- WO 01/05932 It is known from WO 01/05932 that carbohydrates can interact with surfactants to form suspending structures. Such systems generally exhibit even greater d-spacings than the electrolyte-structured expanded L ⁇ -phases, described in EP 0530708.
- the d-rspacings of the sugar-structured systems, described in WO 01/05932 are typically greater than 15nm, and may, for example, be as high as 50nm.
- non-ionic surfactants and or zwitterionic surfactants are strongly preferred.
- structured systems based on non-ionic or zwitterionic surfactants do not readily form stable structured systems, in particular non-ionic surfactants tend to exhibit poor temperature stability at elevated temperatures. They undergo a phase change, on storage under warm conditions, to give non-suspending L 2 - phases.
- WO 01/00780 describes the use of high molecular weight ethoxylates in conjunction with thiocyanates as auxiliary stabilisers inhibiting or preventing loss of structure at elevated temperatures, however thiocyanate is not an acceptable ingredient of products intended for ingestion.
- non-ionic and/or zwitterionic based structured surfactant systems with improved temperature stability which, in a preferred embodiment, are capable of being formulated with pharmacologically acceptable ingredients, and of stably suspending medicaments for internal use.
- non-ionic and/or zwitterionic surfactants having hydrophobic groups with predominantly bent chains are more stable at elevated temperatures than corresponding conventional systems.
- the expression "bent chain” refers to a hydrocarbon chain, which has a dihedral form resulting from the presence of a single non-linear feature, preferably at or near the middle of the chain.
- non-linear features include cis-double bonds, short chain (e.g. methyl or ethyl, or less preferably propyl or butyl) branching and carbonyl groups, and also the hydrophilic, "head group" of the surfactant, when the latter is not attached to one end of the chain (i.e. when, the chain is a secondary alkyl group).
- trans-double bonds, or combinations of two or more non-linear features give chains that are kinked, but are not within the definition of "bent”.
- the non-linear group is preferably located at or near the middle of the chain, i.e. at least two, preferably at least three, more preferably at least four, most preferably at least five, carbon atoms from the non-functional end (or, in the case of secondary alkyl groups, ends) of the chain, and preferably also, in the case of primary alkyl or alkenyl groups, from the functional, i.e. hydrophilic end.
- the invention provides an aqueous based structured surfactant system, having solid-suspending properties and comprising: water; surfactant, said surfactant consisting essentially of at least one non-ionic and/or zwitterionic surfactant , each comprising at least one hydrophobic group and a non-ionic or zwitterionic hydrophilic group; from 0 to50%, based on the weight of surfactant, of acids and/or alcohols having a hydrophobic group and a carboxyl or hydroxyl group respectively; and from 0 to saturation of a water-soluble carbohydrate; said surfactant, acid, alcohol, and carbohydrate being present in proportions adapted to form a pourable structured suspending system; characterised in that at least 30% by weight of said hydrophobic groups are bent chain groups.
- the invention provides a structured surfactant system as aforesaid, for suspending water insoluble pharmaceutical or veterinary active ingredients, which consists essentially of: water; from 0% to saturation of a dissolved carbohydrate; from 0 to 10% by weight, based on the weight of the suspending system, of electrolyte; and from 3 to 10% by weight, based on the weight of the suspending system, of a surfactant mixture consisting of (A) a pharmacologically or veterinarily acceptable surfactant, having an HLB greater than 10, which is preferably an ethoxylated sorbitan ester and (B) a pharmacologically or veterinarily acceptable surfactant, with a HLB less than 10, which is preferably a monoglyceride ester, oleic acid or a phospholipid in a weight ratio of from 10:1 to 1:1, (A):(B).
- a surfactant mixture consisting of (A) a pharmacologically or veterinarily acceptable sur
- the invention provides a method of suspending pharmaceutical or veterinary active ingredients in a structured surfactant system as aforesaid, and suspensions so formed, and methods of preparing such suspensions in dose form for oral use.
- the invention provides a food product or beverage comprising a continuous aqueous liquid phase, and suspended, non-colloidal solid, characterised in that said aqueous phase is a structured surfactant system as aforesaid, which consists essentially of: water; from 25% by weight, based on the weight of the suspending system, to saturation of a dissolved carbohydrate structurant; from 0 to 10% by weight, based on the weight of the suspending system, of electrolyte; and from 3 to 10% by weight, based on the weight of the suspending system, of a surfactant mixture consisting of (A) an edible surfactant, having an HLB greater than 10, which is preferably a ethoxylated sorbitan ester and (B) an edible surfactant, with a pH less than 10, which is preferably a monoglyceride ester or phospholipid, in a weight ratio of from 10:1 to 1:1, (A):(B).
- a structured surfactant system as afores
- the invention provides a stable, pourable suspension comprising from 10 to 50% by weight of an alkaline earth metal soap suspended in a structured surfactant system as aforesaid, containing from 1 to 5% by weight of surfactant consisting essentially of non-ionic surfactants having a mean HLB of from 9 to 14.
- our invention provides a non-ionic structured surfactant system, in which the proportion of hydrophobic groups, which are bent chain, is greater than that corresponding to the maximum or turning point value in the graph of conductivity of against % bent chain groups.
- the invention provides a structured surfactant suspending system, which is preferably an expanded L ⁇ -phase, and which comprises water, a dissolved structurant, which is preferably a carbohydrate, and a surfactant, comprising non-ionic surfactant characterised by a small angle X-ray diffraction peak corresponding to a d-spacing greater than 50nm.
- a structured surfactant suspending system which is preferably an expanded L ⁇ -phase, and which comprises water, a dissolved structurant, which is preferably a carbohydrate, and a surfactant, comprising non-ionic surfactant characterised by a small angle X-ray diffraction peak corresponding to a d-spacing greater than 50nm.
- the hydrophobic groups preferably are aliphatic hydrocarbon groups having more than
- bent chain hydrophobic groups are preferably greater than 40%, more preferably greater than 52%, even more preferably greater than 54%, more preferably still, greater than 60%, most preferably greater than 75%, based on the total weight of hydrophobic groups in the surfactant.
- the preferred bent chain groups are oleyl, erucyl, palmitoleyl, nervonyl and isostearyl.
- the total proportion of surfactant is typically between 2 and 35%, preferably greater than 3% more preferably greater than 5%, even more preferably greater than 6% most preferably greater than 7% by weight, based on the total weight of surfactant and water, but preferably less than 30% more preferably less than 20%, even more preferably less than 15%, most preferably less than 10%.
- the non-ionic surfactants may typically comprise polyglyceryl fatty esters, fatty acid ethoxylates, fatty acid monoalkanolamides, fatty acid dialkanolamides, fatty acid alkanolamide ethoxylates, propylene glycol monoesters, fatty alcohol propoxylates, alcohol ethoxylates, alkyl phenol ethoxylates, fatty amine alkoxylates and fatty acid glyceryl ester ethoxylates.
- non-ionic compounds suitable for inclusion in compositions of the present invention include mixed ethylene oxide/ propylene oxide block copolymers, ethylene glycol monoesters, alkyl polyglycosides, alkyl sugar esters including alkyl sucrose esters and alkyl oligosaccharide esters, sorbitan esters, ethoxylated sorbitan esters, alkyl capped polyvinyl alcohol and alkyl capped polyvinyl pyrrolidone.
- surfactants that are approved for pharmacological use.
- the surfactants preferably have a mean HLB greater than 6.5, more preferably greater than 7.5, even more preferably greater than 8, more preferably still, greater than 8.5, most preferably greater than 9, but less than 13, more prefer ably less than 12, even more preferably less than 12.5, most preferably less than 11.
- the non-ionic surfactant comprises a mixture of at least one relatively high HLB surfactant with at least one relatively low HLB surfactant.
- the high HLB surfactant is preferably an ethoxylated sorbitan ester, such as a 10-30 mole, preferably 15-25 mole ethoxy sorbitan monooleate but could alternatively comprise, for example a sucrose or polyglyceryl ester, or ethoxylated castor oil.
- the ester maybe an ester of a C6 -25 , saturated or unsaturated, bent chain fatty acid, such as oleic, erucic or isostearic. It preferably has an HLB greater than 10, more preferably greater than 12, even more preferably greater than 14, most preferably greater than 14.5, but preferably less than 19, more preferably less than 18, most preferably less than 17.
- the low HLB surfactant is preferably a monoglyceride ester surfactant, such as glyceryl oleate, or, less preferably, a sorbitan ester, a lactic or acetic acid ester of a monoglyceride or a polyglyceryl ester of a fatty acid. Particularly preferred are esters with o- 2 5 hent chain fatty acids such as, oleic, erucic or isostearic.
- the low HLB surfactant preferably has an HLB less than 8, more preferably less than 7, even more preferably less than 6, most preferably less than 5.5, but preferably greater than 2, more preferably greater than 3, most preferably greater than 3.3.
- the weight ratio of low HLB surfactant to high HLB surfactant is preferably less than 2:1, more preferably less than 1.5:1, most preferably less than 1:1, but preferably more than 1:10, more preferably more than 1 :5, most preferably more than 1 3.
- Zwitterionic surfactants are preferably present in a proportion less than 70%, more preferably less than 50%, most preferably less than 40% by weight of the total surfactant.
- the preferred zwitterionic surfactants are phospholipids such as lecithin.
- Lecithin is a diacyl glyceryl phosphato choline
- Fatty acids and fatty alcohols are not normally considered to be surfactants, in relation to aqueous systems, because they are water-insoluble On the HLB scale, they are usually rated as 1. However they are soluble in aqueous non-ionic surfactants and have been found to modify the structure forming potential of higher HLB surfactants in an analogous manner to surfactants with an HLB of about 3 to 5.
- they have bent chain hydrophobic groups, preferably with more than 10, more preferably more than 12 most preferably more than 14 carbon atoms, but less than 30, more preferably less than
- Preferred examples are oleic, palmitoleic, isostearic and erucic acids.
- References herein to mixtures of non-ionic surfactants are to be construed, where the context permits, as embracing mixtures of the aforesaid acids and alcohols with non-ionic surfactants.
- the surfactant system consists essentially of non-ionic and/or zwitterionic surfactant, together with any fatty acids and/ or alcohols.
- anionic, cationic and/or amphoteric surfactant may optionally be present, e.g. up to 30 %, by weight, of the total surfactant, for most purposes it is strongly preferred that anionic surfactants in particular, and also cationic surfactants, be substantially absent. If present they preferably constitute les than 15%, more preferably less than 10%, even more preferably less than 5%, more preferably still less than 2%, most preferably less than 1% by weight of the total surfactant
- the anionic surfactant may, preferably, comprise an alkyl ether sulphate which is preferably the product obtained by ethoxylating a natural fatty or synthetic C ⁇ o- 2 0 e.g. a C ⁇ - 1 4 alcohol with from 1 to 20, preferably 2 to 10 e.g. 3 to 4 ethyleneoxy groups, optionally stripping any unreacted alcohol, reacting the ethoxylated product with a sulphating agent and neutralising the resulting alkyl ether sulphuric acid with a base.
- the term also includes alkyl glyceryl sulphates, and random or block copolymerised alkyl ethoxy/propoxy sulphates.
- the anionic surfactant may also comprise, for example, C 10-2 o e.g. C1 2 -18 alkyl sulphate, C 10-2 o alkyl benzene sulphonate or a C 8 _ 20 e.g. C ⁇ o -2 o aliphatic soap.
- the soap may be saturated or unsaturated, straight or branched chain. Preferred examples include dodecanoates, myristates, stearates, oleates, linoleates, linolenates, behenates, erucates and palmitates and coconut and tallow soaps.
- the surfactant may also include other anionic surfactants, such as olefin sulphonates, paraffin sulphonates, taurides, isethionates, ether sulphonates, ether carboxylates, sarcosinates, aliphatic ester sulphonates e.g. alkyl glyceryl sulphonates, sulphosuccinates or sulphosuccinamates.
- anionic surfactants such as olefin sulphonates, paraffin sulphonates, taurides, isethionates, ether sulphonates, ether carboxylates, sarcosinates, aliphatic ester sulphonates e.g. alkyl glyceryl sulphonates, sulphosuccinates or sulphosuccinamates.
- any anionic surfactant is typically sodium but may alternatively be potassium, lithium, calcium, magnesium, ammonium, or an alkyl ammonium having up to 6 aliphatic carbon atoms including ethylammonium, isopropylammonium, monoethanolammonium, diethanolammonium, and triethanolammonium.
- Ammonium and ethanolammonium salts are generally more soluble than the sodium salts. Mixtures of the above cations maybe used.
- compositions of the invention comprise a carbohydrate. It has been found that, even where the surfactant system is sufficient to form a structured suspending system in the absence of carbohydrate, added carbohydrate tends to increase the yield point and suspending power and stability of the system.
- the aqueous structured systems formed by the interaction of surfactants with carbohydrates, include systems, which are believed to be in the form of an expanded L ⁇ - phase. They include novel systems having an even wider d-spacing than the typical elecfrolyte-structured expanded L ⁇ -phases described in EP 0 530708.
- the systems of the present invention comprise structures, which preferably show d- spacings greater than 20nm, more preferably greater than 50nm, even more preferably greater than 51nm, more preferably still, greater than 70nm, most preferably greater than 90nm.
- the d- spacing is less than 300nm, more preferably less than 200nm, most preferably less than 150nm.
- d-spacings greater than 300nm, but such d-spacings are difficult to measure accurately, using conventional X-ray diffractometers, due to their proximity to the reference beam.
- the above d-spacings relate to the principal, only substantial or sole peak exhibited by the structured system, in the absence of suspended matter, at least above Inm.
- the carbohydrate is preferably a mono or, more preferably, disaccharide sugar, most preferably sucrose, but could for example be fructose, maltose, glucose or invert sugar.
- sugars which can be used, include, for example, mannose, ribose, galactose, lactose, allose, altrose, talose, gulose, idose, arabinose, xylose, lyxose, erythrose, threose, acrose, rhamnose, fucose, glyceraldehyde, stachyose, agavose and cellobiose.
- the carbohydrate may be a tri- or tetra-saccharide or, less preferably, a water soluble polysaccharide such as soluble starch, or a water soluble gum.
- carboxylic acids and their salts, which can be obtained by oxidising sugars, e.g. gluconic acid, mannic acid, ascorbic acid and alginates, or alcohols obtained by reducing sugars such as sorbitol, mannitol or inositol.
- the levels of carbohydrate may be sufficiently high to inhibit microbiological growth in the medium and sufficient to act as an effective biodegradable, non-allergenic preservative for the composition.
- the carbohydrate may additionally mask the taste of the active ingredient, and render the composition more palatable.
- the carbohydrate may be present, optionally, in concentrations up to saturation, preferably greater than 3%, more preferably greater than 5%, even more preferably greater than 10%, most preferably greater than 15% by weight.
- concentration of carbohydrate is less than 75%, by weight, preferably less than 50%, most preferably less than 40%, by weight.
- the composition may optionally contain an electrolyte, in concentrations up to saturation.
- concentration of electrolyte is preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, e.g. 0 to 4%, by weight.
- the electrolyte is typically sodium chloride, but could, for example, alternatively or additionally, be or comprise, sodium carbonate, potassium chloride, sodium phosphate, or sodium citrate.
- electrolytes may be required in order to form suspending systems, when the concentration of surfactant is too low, and/or its HLB is too high to form a suspending system on its own, and there is not enough carbohydrate present to impose a structure.
- the suspending medium of the invention may be used to suspend any medicament, which is insufficiently soluble in water to be conveniently dosed as an aqueous solution.
- the suspended material may comprise one or more antibiotic, analgesic, antiviral, anthelmintic, antacid, anticonvulsant, antifungal, tranquiliser, sedative, anti- inflammatory, anti-histamine or tonic. It can be used to suspend animal food supplements, such as selenium particles, for veterinary use.
- the suspended material may have any convenient particle size, and is not limited to micron-sized particles, like colloidal systems. This allows slower release in the body, as well as lower manufacturing costs.
- a particular advantage of using structured surfactants to suspend pharmacologically active ingredients is the possibility of suspending particles of widely different sizes, allowing a control over the release rate of the active substance, or the relative release rates of two or more active substances, an effect that has hitherto only been possible using encapsulation.
- the invention provides a pharmaceutical or veterinary suspension comprising a pharmacologically or veterinarily acceptable structured surfactant and suspended particles of at least one pharmacological or veterinary active substance, said particles comprising at least two populations differentiated with respect to size and including a first population, of non-colloidal particles comprising at least 10%, preferably at least 20%, more preferably at least 30% by weight, based on the total weight of the particles, and a second population of particles comprising at least 10%, preferably at least 20%, more preferably at least 30%, by weight, based on the total weight of the particles, wherein said first population has a mean particle size at least ten times, preferably at least fifty times, more preferably at least 100 times, even more preferably at least 200 times, most preferably at least 500 times the mean particle size of said second population.
- alkaline earth metal soap the latter will normally be a calcium soap, although the invention is equally applicable to soaps of other alkaline earth metals such as magnesium, barium, strontium and zinc.
- the soap is preferably a C ⁇ _. 25 straight or branched chain, saturated or unsaturated aliphatic soap, but is more preferably straight chain and more preferably saturated. It is particularly preferred that the soap has more than 12, more preferably more than 14, most preferably more than 16 carbon atoms. It is further preferred that the soap has less than 24, more preferably less than 22, most preferably less than 20 carbon atoms. The most widely used soap of this type, by a large margin, is calcium stearate. Other soaps include the alkaline earth metal palmitates, oleates, behenates, arachidates, linoleates and linolenates.
- the soap is preferably present in an amount greater than 20%, more preferably greater than 25%, even more preferably greater than 30%, more preferably still, greater than 35%o, most preferably greater than 37%, but preferably less than 48%, more preferably less than 45% by weight based on the weight of the suspension.
- the total concentration of surfactant, for use in soap suspensions is preferably less than 5%, more preferably less than 4%, most preferably less than 3.5% by weight, based on the weight of the suspension, but more than 1%, preferably more than 1.5%, most preferably more than 2%.
- the suspension may alternatively, for example, be a food or beverage, a detergent, in which the suspended particles may comprise a builder and/or silicone antifoam, a hard surface cleaner comprising a suspended abrasive, a personal care formulation, comprising personal care active ingredients, such as talc, titanium oxide, vegetable oil, silicone oil, exfoliants, pigments and topical medicaments, an agrochemical composition comprising e.g. pesticides, weed-killers or fertilisers or a suspension of seeds or other plant propagules, such as corms, tubers, bulbs , calli or pieces of merristematic tissue for sowing or propagation.
- a detergent in which the suspended particles may comprise a builder and/or silicone antifoam
- a hard surface cleaner comprising a suspended abrasive
- a personal care formulation comprising personal care active ingredients, such as talc, titanium oxide, vegetable oil, silicone oil, exfoliants, pigments and topical medicaments
- a paediatric analgesic suspension comprised:
- the product was a stable, non-sedimenting suspension.
- the suspended material had particles ranging in size from 5 to 100 ⁇ , compared to a narrow range of about 7 ⁇ , which is required to make colloidal dispersions.
- EXAMPLE II An animal feed supplement comprised:
- the above formulation was a clear thin structured liquid with a d-spacing of about 120nm, and was stable after three weeks storage
- a fruit drink comprised:
- composition consisting of:
- the mixture was a stable, pourable, spherulitic suspension with good compatibility with cement.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Animal Behavior & Ethology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
- Fodder In General (AREA)
- General Preparation And Processing Of Foods (AREA)
- Cosmetics (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004257454A AU2004257454B2 (en) | 2003-07-15 | 2004-07-14 | Structured surfactant systems |
JP2006519996A JP2007527313A (en) | 2003-07-15 | 2004-07-14 | Organized surfactant system |
EP04743392A EP1656114A1 (en) | 2003-07-15 | 2004-07-14 | Structured surfactant systems |
US10/564,147 US20060178441A1 (en) | 2003-07-15 | 2004-07-14 | Structured surfactant systems |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0316467A GB0316467D0 (en) | 2003-07-15 | 2003-07-15 | Structured surfactant systems |
GB0316467.0 | 2003-07-15 | ||
GB0317252.5 | 2003-07-24 | ||
GB0317252A GB0317252D0 (en) | 2003-07-24 | 2003-07-24 | Structured surfactant systems |
GB0319856A GB0319856D0 (en) | 2003-08-23 | 2003-08-23 | Structured surfactant systems |
GB0319856.1 | 2003-08-23 | ||
GB0321036A GB0321036D0 (en) | 2003-09-09 | 2003-09-09 | Structured surfactant systems |
GB0321036.6 | 2003-09-09 | ||
GB0325427.3 | 2003-10-31 | ||
GB0325427A GB0325427D0 (en) | 2003-10-31 | 2003-10-31 | Structured surfactant systems |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005007133A1 true WO2005007133A1 (en) | 2005-01-27 |
Family
ID=34084762
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2004/003051 WO2005007133A1 (en) | 2003-07-15 | 2004-07-14 | Structured surfactant systems |
Country Status (6)
Country | Link |
---|---|
US (1) | US20060178441A1 (en) |
EP (1) | EP1656114A1 (en) |
JP (1) | JP2007527313A (en) |
KR (1) | KR20060065631A (en) |
AU (1) | AU2004257454B2 (en) |
WO (1) | WO2005007133A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008023145A1 (en) * | 2006-08-22 | 2008-02-28 | Innovation Deli Limited | Structured cleaning compositions |
WO2009098469A1 (en) * | 2008-02-06 | 2009-08-13 | Biosuspensions Limited | Novel compositions and uses thereof |
WO2010138539A2 (en) * | 2009-05-27 | 2010-12-02 | Elan Pharma International Ltd. | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4793319B2 (en) * | 2007-05-15 | 2011-10-12 | 大正製薬株式会社 | Beverages containing sucrose fatty acid esters |
US8708947B2 (en) * | 2011-02-24 | 2014-04-29 | Kimberly-Clark Worldwide, Inc. | Tampons including moisture-activated compositions |
US8663151B2 (en) * | 2011-02-24 | 2014-03-04 | Kimberly-Clark Worldwide, Inc. | Personal care devices including moisture-activated compositions |
GB201202333D0 (en) * | 2012-02-10 | 2012-03-28 | Stepan Co | Structured surfactant suspending systems |
US9668474B2 (en) * | 2012-02-10 | 2017-06-06 | Stepan Company | Structured surfactant suspending systems |
CA3072937A1 (en) | 2017-08-14 | 2019-02-21 | Stepan Company | Agricultural compositions containing structured surfactant systems |
WO2023154747A1 (en) * | 2022-02-09 | 2023-08-17 | Stepan Company | Suspending systems constructed from hydrotropes |
Citations (4)
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EP0414549A2 (en) * | 1989-08-24 | 1991-02-27 | Albright & Wilson Limited | Liquid cleaning compositions and suspending media |
US5964692A (en) * | 1989-08-24 | 1999-10-12 | Albright & Wilson Limited | Functional fluids and liquid cleaning compositions and suspending media |
WO2001000780A1 (en) * | 1999-06-24 | 2001-01-04 | Rhodia Consumer Specialties Limited, Trading As Albright & Wilson Surfactants Europe | Surfactant emulsions and structured surfactant systems |
WO2002002730A1 (en) * | 2000-07-06 | 2002-01-10 | Huntsman International Llc | Solid-suspending systems |
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US3957662A (en) * | 1972-08-08 | 1976-05-18 | Hoffmann-La Roche Inc. | Pharmaceutical lubricants |
AU663061B2 (en) * | 1990-11-23 | 1995-09-28 | Unilever Plc | Use of mesomorphic phases in food products |
US6426333B1 (en) * | 1996-09-19 | 2002-07-30 | Merial | Spot-on formulations for combating parasites |
EP1203068B1 (en) * | 1999-07-17 | 2008-09-03 | Huntsman International Llc | Structured surfactant systems |
US20040235702A1 (en) * | 1999-07-17 | 2004-11-25 | Huntsman International Llc | Structured surfactant systems |
-
2004
- 2004-07-14 EP EP04743392A patent/EP1656114A1/en not_active Withdrawn
- 2004-07-14 JP JP2006519996A patent/JP2007527313A/en active Pending
- 2004-07-14 WO PCT/GB2004/003051 patent/WO2005007133A1/en active Application Filing
- 2004-07-14 US US10/564,147 patent/US20060178441A1/en not_active Abandoned
- 2004-07-14 AU AU2004257454A patent/AU2004257454B2/en not_active Ceased
- 2004-07-14 KR KR1020067001027A patent/KR20060065631A/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0414549A2 (en) * | 1989-08-24 | 1991-02-27 | Albright & Wilson Limited | Liquid cleaning compositions and suspending media |
US5964692A (en) * | 1989-08-24 | 1999-10-12 | Albright & Wilson Limited | Functional fluids and liquid cleaning compositions and suspending media |
WO2001000780A1 (en) * | 1999-06-24 | 2001-01-04 | Rhodia Consumer Specialties Limited, Trading As Albright & Wilson Surfactants Europe | Surfactant emulsions and structured surfactant systems |
WO2002002730A1 (en) * | 2000-07-06 | 2002-01-10 | Huntsman International Llc | Solid-suspending systems |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008023145A1 (en) * | 2006-08-22 | 2008-02-28 | Innovation Deli Limited | Structured cleaning compositions |
US9254264B2 (en) | 2008-02-06 | 2016-02-09 | Biosuspensions Limited | Compositions and uses thereof |
WO2009098469A1 (en) * | 2008-02-06 | 2009-08-13 | Biosuspensions Limited | Novel compositions and uses thereof |
WO2009098475A1 (en) * | 2008-02-06 | 2009-08-13 | Biosuspensions Limited | Structured surfactant systems and uses thereof |
WO2010138539A2 (en) * | 2009-05-27 | 2010-12-02 | Elan Pharma International Ltd. | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
AU2010254180B2 (en) * | 2009-05-27 | 2015-08-27 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
WO2010138539A3 (en) * | 2009-05-27 | 2011-09-29 | Elan Pharma International Ltd. | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US9345665B2 (en) | 2009-05-27 | 2016-05-24 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US9974746B2 (en) | 2009-05-27 | 2018-05-22 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US9974748B2 (en) | 2009-05-27 | 2018-05-22 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US9974747B2 (en) | 2009-05-27 | 2018-05-22 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US11253478B2 (en) | 2009-05-27 | 2022-02-22 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US11717481B2 (en) | 2009-05-27 | 2023-08-08 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
Also Published As
Publication number | Publication date |
---|---|
AU2004257454B2 (en) | 2010-12-23 |
EP1656114A1 (en) | 2006-05-17 |
KR20060065631A (en) | 2006-06-14 |
AU2004257454A1 (en) | 2005-01-27 |
US20060178441A1 (en) | 2006-08-10 |
JP2007527313A (en) | 2007-09-27 |
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