WO2003020319A1 - Composition support d'emulsion eau dans huile - Google Patents

Composition support d'emulsion eau dans huile Download PDF

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Publication number
WO2003020319A1
WO2003020319A1 PCT/SE2002/001572 SE0201572W WO03020319A1 WO 2003020319 A1 WO2003020319 A1 WO 2003020319A1 SE 0201572 W SE0201572 W SE 0201572W WO 03020319 A1 WO03020319 A1 WO 03020319A1
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Prior art keywords
oil
carrier composition
oil phase
phase
composition according
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PCT/SE2002/001572
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English (en)
Inventor
Andreas Fischer
Christina Adde
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Lipocore Holding Ab
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Publication of WO2003020319A1 publication Critical patent/WO2003020319A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/064—Water-in-oil emulsions, e.g. Water-in-silicone emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/31—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/925—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of animal origin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention is related to a new w/o-emulsion carrier composition for administration of biologically active substances, and in particular for controlled release of said bioactive substances in vivo.
  • Controlled release systems aim at maintaining nearly constant in vivo therapeutic drug concentrations for an extended period of time.
  • Examples are depot systems based on polymer systems from which the active compound is released through diffusion from a non- biodegradable matrix, or through biodegradation of the matrix, or, in the case of water-soluble polymers, through dissolution of the polymer in the biological fluids.
  • the non-biodegradable polymers do not undergo any significant change in the body.
  • biodegradable polymer systems are a potential risk of causing irritation to the site of implantation, which is also the case for water-soluble polymers during their dissolution and degradation in the body.
  • Another disadvantage with polymeric systems is related to their capacity of incorporation of active substances, which in many cases is low and they are therefore often restricted to highly potent drug substances.
  • a practical problem is that different drugs require different polymer systems to meet their respective specific requirements in terms of incorporation level and release criteria.
  • Lipid oil systems such as solutions or suspensions in triglyceride oils, so called fixed oils (USP XXIII) , are also used for sustained release. Disadvantages with said systems are that only a limited number of compounds can be incorporated, including drugs which have been esterified with fatty acyl groups to pro-drugs, and that the release rate of such compounds cannot be influenced. This implies that said systems are of limited value as parenteral depot systems .
  • the use of other non- dispersed lipid carriers, i.e. oily vehicles, in pharmaceutical products is quite limited.
  • the use of such systems for oral delivery is based on the self-emulsifying properties of the lipid system and an immediate release of the active compound in the gastrointestinal tract .
  • lipid systems than the oils and oily vehicles are dispersions, such as lipid emulsions and liposomes, which after intravenous administration offer only limited sustained release of incorporated drug substances.
  • dispersions such as lipid emulsions and liposomes
  • lipid emulsions and liposomes which after intravenous administration offer only limited sustained release of incorporated drug substances.
  • there are reports in the literature of intramuscularly or subcutaneously injected liposomes which do work as sustained release delivery systems, but the recognised difficulties are low encapsulation capacity and poor storage stability.
  • thermodynamically stable lipid systems have been developed. They are, however, based on the interaction of water with amphiphilic lipids to form stable liquid crystalline phases. Such systems have hitherto found very limited use in pharmaceutical applications.
  • WO 01/66086 in the name of Lipocore Holding AB, refers to a lipid carrier for controlled release of a bioactive substance, the- structure of which is retained in an aqueous environment.
  • the carrier composition comprises a triglyceride oil, a polar lipid selected from the group of phosphatidyl- ethanolamine and monohexosylcer mide, and ethanol.
  • the carrier consists entirely of a lipid, or oil, phase, and is therefore well suited for incorporating lipophilic substances; the carrier is, however, incapable of dissolving lipophobic, hydrophilic substances .
  • LMCs lipid matrix carriers
  • the LMCs are described as globular structures with a diameter ranging from about 500 to about 100,000 nm composed of a hydro- phobic compound and an amphiphatic compound. Said globular structures are prepared in a cumbersome process involving dissolution of the lipid mixture in an organic solvent, agita- tion of the organic solution in an aqueous phase and evaporation of the organic solvent.
  • the polar lipid used in the preparation of w/o-emulsions is in all examples EPC, that is egg phosphati- dylcholine.
  • US 5,912,271 in the name of Astra AB, refers to a composition comprising one or more local anaesthetic agents, one or more polar lipids, a triacylglycerol and optionally water, with the objective to obtain faster onset of anaesthesia.
  • the preferred sphingolipid is sphingomyelin or products derived from sphingomyelin. In all examples containing sphingolipid materials the sphingomyelin content of the materials lies between 60 and 98 %.
  • JP2000-119178A in the name of Shionogi & Co., Ltd., refers to a composition comprising a ceramide, monohydric lower alcohol, oil and water, which composition is capable of forming a transparent solution in an equilibrium state, i.e. not an emulsion.
  • the disclosed ceramides can all be dissolved in the composition without heating.
  • Preferred ceramides are ceramide 1, ceramide 3 and ceramide 6 obtained from Cosmoferm B.V., Delft, The Netherlands .
  • Said ceramides do not have a glycosyl moiety attached to the sphingoid group, that is they are not glycosyl- ceramides .
  • the disclosed composition is intended for topical use .
  • Safranine O as a marker, substance, from carrier compositions of the invention.
  • Figure 2 shows the dissolution profiles obtained with pyridoxine hydrochloride as a marker substance, from carrier compositions of the invention.
  • a w/o-emulsion carrier of the composition stated below has the ability to retain its cohesive structure with incorporated compounds in an aqueous environment, and therefore can be used for controlled release, such as sustained release, of an incorporated bioactive substance.
  • the oil phase of the w/o-emulsion carrier of the invention is based on lipid components, which are either normal components of the human cells and membranes, or present in significant amounts in the human diet. This means that said lipids are biocompatible with human tissues and are metabolised in the same way as the corresponding endogenous lipids.
  • the invention refers to a w/o-emulsion carrier composition for controlled release of a bioactive substance, comprising an oil phase and an aqueous phase dispersed in the continuous oil phase, which is characterised, m that the oil phase contains at least one non-polar oil and monoglycosylceramide, whereby the carrier composition is able to form a cohesive structure which is retained in an aqueous environment .
  • the invention also refers to a w/o-emulsion carrier composition for controlled release of a bioactive substance, comprising an oil phase and an aqueous phase dispersed in the continuous oil phase, which is characterised in that the oil phase contains at least one non-polar oil, monoglycosylceramide, and ethanol, whereby the carrier composition is able to form a cohesive structure which is retained in an aqueous environmen .
  • cohesive structure which is retained in an aqueous environment is meant that the carrier composition forms a macroscopically continuous, typically single, body in the aqueous medium.
  • This cohesive structure in aqueous media differs significantly from the discrete lipid particles, which are normally obtained when a lipid emulsion is dispersed into an aqueous environment.
  • the cohesive composition of the present invention is designed to be administered as such, and not to be dispersed or suspended in any media prior to administration.
  • the aqueous phase is dispersed as microscopic aqueous droplets in the continuous oil phase.
  • Aqueous phase refers to any aqueous solution or dispersion with water as a solvent or dispersing medium.
  • the non-polar oil can be a triglyceride oil, a mineral oil or a mixture thereof.
  • a suitable oil, as exemplified below, in the w/o-emulsion carrier composition of the invention is a triglyceride oil, or in other words a triacylglycerol oil, wherein the acyl groups are derived from unsaturated or saturated fatty acids or hydroxy fatty acids having 8-22 carbon atoms .
  • the triglyceride oil can be selected from the group of natural vegetable oils consisting of, but not limited to, almond oil, coconut oil, maize oil, wheat germ oil, soybean oil, sesame oil, palm oil, safflower oil, evening primrose oil, sunflower oil, rape seed oil, linseed oil, corn oil, cottonseed oil, peanut oil, olive oil, or from the group of fractionated oils consisting of, but not limited to, refined vegetable oils, and medium chain triglyceride oil (also called fractionated coconut oil) , or from the group of semi-synthetic oils consisting of, but not limited to, acetylated monoglyceride oils, or from the group of animal oils, consisting of, but not limited to, butter oil, marine oils, such as fish oil.
  • natural vegetable oils consisting of, but not limited to, almond oil, coconut oil, maize oil, wheat germ oil, soybean oil, sesame oil, palm oil, safflower oil, evening primrose oil, sunflower oil, rape
  • the triglyceride oil is preferably selected from the group consisting of medium chain triglyceride oil, sesame oil, evening primrose oil, sunflower oil, coconut oil, soybean oil, corn oil, fish oil, or a mixture thereof.
  • mineral oils are hydrocarbon oil, liquid paraffin. Any mixture of oils derived from any of the mentioned groups can also be used in the carrier composition of the invention.
  • the non-polar oil is preferably selected from the oils accepted for parental or oral use according to national and international regulatory authorities .
  • Monoglycosylceramides are monosaccharide-containing derivatives of ceramides. Ceramides are N-acylated sphingoids . A sphingoid is a long-chain aliphatic amino alcohol. A monoglycosylceramide can be represented by the general formula I
  • R' and R" represent optionally substituted hydrocarbon chains .
  • sphinganine The basic chemical structure of a sphingoid is represented by the compound originally called dihydrosphingosine, now referred to as sphinganine, or more specifically 2-amino-l,3- octadecanediol .
  • sphinganine homologues which can differ in chain-length, degree of unsaturation and presence of substituents, such as hydroxyl, oxo, methyl, etc.
  • sphinganine homologues are: -sphingenine (sphingosine) , icosasphinganine (C20-dihydrosphingosine) , 4- hydroxysphinganine (phytosphingosine) , 4-hydroxyicosasphinganine (C20-phytosphingosine) , 4-hydroxy-8-sphingenine (dehydrophyto- sphingosine) , 4, 8-sphingadienine (sphingadienine) , 4-hexadeca- sphingenine (C16-sphingosine) , hexadecasphinganine (C16-dihydro- sphingosine) and heptadecasphingenine (Cl7-sphingosine) .
  • the acyl chains linked to the amide nitrogen of naturally occurring ceramides can have a chain length from about 10 to 28 carbon atoms, more often from 16 to 26, and may contain one or more double bonds, and may contain " one or more substitu- ents, such as hydroxyl, oxo and lower alkyl, such as methyl.
  • synthetically produced ceramides can have much more diverse acyl chains linked to the amide nitrogen, in terms of chain length, double bonds, substituents, etc.
  • the invention especially refers to a carrier composition wherein the acyl chains linked to the amide nitrogen of the monoglycosylceramides are derived from unsaturated or saturated fatty acids having 10-28 carbon atoms (that is R" having 9-27 carbon atoms) .
  • the composition contains monoglycosylceramides wherein the sphingoid base has 6-28 carbon atoms (that is R' has 3-25 carbon atoms) .
  • Preferred monoglycosylceramides according to the invention are monohexosylceramides, CMH, and in particular monoglucosylceramide or monogalactosylceramide.
  • Monohexosyl- ceramide can be described by the following formula II
  • Monohexosylceramides can be of synthetic or semi-synthetic origin, or obtained from milk or other dairy products, or from animal organs or materials, such as brain, spleen, liver, kidney, erythrocytes , or from plant sources .
  • Formula III refers to a monoglucosylceramide based on sphingenine
  • R 1 and R 2 represent optionally substituted hydrocarbon chains .
  • sphingoids examples include hexadeca- sphingenine, hexadecasphinganine, heptadecasphingenine and sphinganine .
  • the acyl chains linked to the amide nitrogen of the ceramides range in chain length from about 12-28 carbon atoms, where the four most common acyl chains, C16.0, C22:0, C23.0 and C24.0, account for about 80 % by weight, as determined by gas chromatography.
  • the average acyl chain length is about 22 carbon atoms and the fraction of unsaturated acyl chains is about 5 % by weight, as determined by gas chromatography.
  • the composition contains monohexosylceramides obtainable from bovine milk.
  • An advantage of the monoglycosylceramides over phospho- lipids and many other polar lipids is the relatively high chemical stability due to a less tendency of oxidation and hydrolysis .
  • the release properties of the w/o-emulsion carrier system of the invention is depending on the composition of the oil phase, the composition of the aqueous phase and the ratio aqueous phase/oil phase, and can be controlled by selecting the proportions of the oil phase components and the aqueous phase components, and selecting the ratio aqueous phase/oil phase (the w/o ratio) . Said proportions can also be selected to optimise the incorporation of specific bioactive substances, or to control the viscosity of the carrier composition.
  • a w/o-emulsion carrier composition which is suitable for parenteral administration, e.g. subcutaneous, intraperi- tonal, intramuscular or intradermal injection, or for oral administration, can preferably consist of an oil phase of 30- 99.9 % by weight of non-polar oil, such as a triglyceride oil or a suitable mineral oil, in combination with 0.1-40 % by weight of monoglycosylceramide, and up to 30 % by weight of ethanol, and an aqueous phase, in a w/o ratio of up to 80/20 by weight.
  • non-polar oil such as a triglyceride oil or a suitable mineral oil
  • the carrier composition can consist of an oil phase of 60-99.9% by weight of non-polar oil, such as a tri- glyceride oil or a suitable mineral oil, in combination with 0.1-40 % by weight of monoglycosylceramide, and an aqueous phase, in a w/o ratio of up to 80/20 by weight.
  • non-polar oil such as a tri- glyceride oil or a suitable mineral oil
  • aqueous phase in a w/o ratio of up to 80/20 by weight.
  • a preferred w/o ratio is 10/90 - 70/30, by weight, of the respective phases.
  • the non-polar oil should preferably be liquid at ambient temperature.
  • the upper limit of the content of monoglycosylceramide is restrained by the possibility of achieving a homogeneous oil phase during the preparation of the carrier and by the high viscosity obtained in the oil phase and the carrier at too high contents thereof. If the oil phase has a high viscosity, it is difficult to disperse the aqueous phase in the oil phase, and for parenteral formulations a carrier of high viscosity is not practical, but a carrier of high viscosity can be used in oral formulations .
  • the content of ethanol can be varied.
  • a high content of ethanol will facilitate the achievement of a homogeneous oil phase and lower the viscosity of both the oil phase and the w/o- emulsion carrier.
  • the upper limit of the w/o ratio is restrained by the possibility of achieving a homogeneous w/o-emulsion. At too high w/o ratios the oil phase cannot disperse the entire aqueous phase. The maximum w/o ratio differs with the composition of the oil phase and the aqueous phase .
  • the content of monoglycosylceramide, as well as the w/o ratio may be adjusted.
  • the performance of the w/o-emulsion carrier composition in aqueous environments is also depending on the choice of non-polar oil, the content of ethanol and the presence of possible excipients .
  • a high content of monoglycosylceramide may be necessary for the carrier to stay cohesive in an aqueous environment .
  • the present invention refers to a w/o-emulsion carrier composition wherein the content of monoglycosylceramide is 0.1-20 % by weight of the oil phase, preferably 0.2-10 %.
  • the composition of the invention can also contain one or more excipients in an amount not negatively affecting the bioactive substance or the release thereof .
  • Excipient can be defined as any component, other than the bioactive substance, included in the carrier composition.
  • Excipients can be incorporated for the purpose of modifying physical or chemical properties of the composition, or as inert bulk, or volume, materials.
  • the excipient can contribute to such properties of the carrier composition as stability, solubility, polarity, viscosity, release properties, appearance, patient acceptability, and ease of production.
  • Excipients are for instance antimicrobial preservatives, antioxidants, stabilisers, emulsifiers, complexing agents, thickeners and penetration enhancers .
  • excipients can be mentioned glycerol, ethylene glycol, polyethylene glycols, propylene glycol, polypropylene glycols, fatty alcohols, sterols, such as cholesterol, monoglycerides, diglycerides, tetraglycol, propylene carbonate and copolymers of polyethylene oxide and polypropylene oxide, or a mixture thereof .
  • the w/o-emulsion carrier of the present invention is prepared in a relatively easy manner with few constituents, compared to other common w/o-emulsions and other depot systems.
  • a mixture of monoglycosylceramide, non-polar oil, and optionally ethanol is stirred in a sealed vial at an elevated temperature, typically 80 °C, until a homogeneous oil phase has been obtained, normally for 10 minutes. After the heating the oil phase is allowed to cool whereupon a macroscopically homogeneous, turbid oil phase of semi-solid consistency is formed. The aqueous phase is then added to the oil phase, and dispersed into the oil phase simply by supplying mechanical energy at a temperature from 0 °C to about 60 °C. A macroscopically homogeneous w/o-emulsion, often of a cream-like consistency, is then obtained.
  • aqueous phase does not have to be heated during the preparation, which is a substantial advantage when thermally labile substances are to be incorporated into the aqueous phase .
  • Another advantage in the preparation of the carrier composition of the invention is that no organic solvents, other than optionally ethanol, is used during the preparation. Organic solvents may be detrimental to the native antigenic properties of vaccines, leading to undesirable immune responses upon immunisation.
  • the common feature of the different compositions of the present invention is the coherent appearance of the carrier composition when brought into contact with different aqueous media.
  • aqueous media such as distilled water, 0.1 M HC1 (pH 1), 0.1 M NaOH (pH 13), buffer solution that mimics the salt concentration and pH of human blood and interstitial fluids (20 mM Hepes, 150 M NaCl, 0.01 % w/w NaN 3 , pH 7.4), solutions that mimic the salt concentration, pH and pepsin concentration of human gastric juice (2.0 g NaCl, 3.2 g pepsin, 80 ml 1 M HC1, distilled water up to 1000 ml) and an acidic saline (70 mM NaCl, pH 1.0) .
  • the fact that the carrier composition of the present invention retains its cohesive structure when added to such diverse aqueous media as described above, makes it possible to use the carrier composi- tion for controlled release in a number of different applications .
  • the invention refers to the use of a w/o-emulsion carrier as described for the preparation of a depot formulation for injection for controlled release of a bioactive substance in vivo.
  • Preferred ways of administration are by subcutaneous, intraperitonal, intramuscular or intradermal injection.
  • the results of the sustained release examples indicate that the w/o- emulsion carrier composition can act as a parenteral depot system for several months in vivo.
  • the use of the invention for parenteral depot applications is obvious, but other uses are also obvious to the man skilled in the art.
  • the w/o-emulsion carrier composition can for example be used for oral controlled release delivery of a drug substance.
  • a specific aspect of the invention is therefore the use of a w/o-emulsion carrier according to the invention for the preparation of an oral formulation for controlled release of a bioactive substance in vivo. Because of the coherent appearance in aqueous solutions mimicing the human gastric juice it is furthermore appealing to think of applications where the carrier protects the drug substances in the gastric environment.
  • w/o-emulsion carrier of the present invention is for taste masking of drugs in pharmaceutical products for oral administration.
  • the invention also refers to a pharmaceutical formulation for controlled release of a bioactive substance, which formulation consists of a w/o-emulsion carrier composition as previously described, and a bioactive substance dissolved or dispersed in said carrier.
  • the invention refers to a pharmaceutical formulation wherein the w/o-emulsi ⁇ n carrier composition consists of an oil phase of 30-99.9 % by weight ot non-polar oil, such as a triglyceride oil or a suitable mineral oil, in combination with 0.1-40 % by weight of monoglycosylceramide, and up to 30 % by weight of ethanol, and an aqueous phase, in a w/o ratio of up to 80/20 by weight, in addition to the bioactive substance .
  • ot non-polar oil such as a triglyceride oil or a suitable mineral oil
  • the invention refers to a pharmaceutical formulation wherein the w/o-emulsion carrier composition consists of an oil phase of 60-99.9% by weight of non-polar oil, such as a triglyceride oil or a suitable mineral oil, in combination with 0.1-40 % by weight of monoglycosylceramide, and an aqueous phase, in a w/o ratio of up to 80/20 by weight, in addition to the bioactive substance.
  • a pharmaceutical formulation of the invention can in addition contain one or more excipients in combination with the carrier of the invention.
  • the carrier composition of the present invention is by no means limited to the ability of the carrier composition to dissolve the bioactive substance in the aqueous phase .
  • Other bioactive substances which are not soluble in the aqueous phase may be incorporated into the oil phase, by dissolving and/or dispersing the substance in the oil phase, see Example 26.
  • the purpose of an aqueous phase in such cases is merely to make the carrier cream-like or to alter the appearance and performance of the carrier.
  • the semi-solid consistency, which can be obtained, of the carrier composition makes it possible to disperse and suspend solid crystalline or amorphous structures homogeneously into the carrier composition and prevent sedimentation upon storage, see Example 27. This is a possible way of incorporating bioactive substances which are neither soluble in the aqueous phase nor the oil phase.
  • the carrier composition is also appealing to use for incorporating a multitude of bioactive substances in the same formulation due to the ability of the carrier to dissolve both water, oil and ethanol soluble drugs.
  • the bioactive substance can be defined as a biologically active substance, or material, which can be used within human or veterinary medicine for diagnosis, treatment or prevention of disease, or to affect the structure or function of the human or animal body.
  • the invention especially refers to a pharmaceutical formulation wherein the bioactive substance is selected from the group consisting of neuroleptic, antidepressive, antipsychotic, antibiotic, antimicrobial, antiviral, anti-inflammatory, antitumour, nootropic, psychotomimetic and anti-Parkinson drugs, drugs used in bone disorders, contraceptives, psychostimulants, lipids, steroids, hormones, proteins, peptides, amino acids, minerals and vitamins.
  • the bioactive substance is selected from the group consisting of neuroleptic, antidepressive, antipsychotic, antibiotic, antimicrobial, antiviral, anti-inflammatory, antitumour, nootropic, psychotomimetic and anti-Parkinson drugs, drugs used in bone disorders, contraceptives, psychostimulants, lipids, steroids, hormones, proteins, peptides, amino acids, minerals and vitamins.
  • a pharmaceutical formulation can comprise more than one bioactive substance.
  • Example 7 Castor oil, a macroscopically homogeneous w/o-emulsion of cream-like consistency.
  • monoglycosylceramide was used monohexosylcer mide, CMH, prepared from whey concentrate by means of chromatographic fractionation to a purity of >99 % from Lipid Technologies Provider AB, Sweden.
  • the non-polar oils were: MCT oil (medium chain triglyceride oil) from Croda Oleochemicals, England; Evening primrose oil (chromatographic fractionated) from Ontario LipidTeknik AB, Sweden;
  • Example 8 Fish oil 0.0581 g CMH was mixed with 0.9992 g fish oil and 0.1160 g ethanol to form the oil phase. 0.7887 g of distilled water was added to the oil phase. RP oil phase; CMH/oil/ethanol : 5.0/85.2/9.9 %w/w, w/o: 40.2/59.8 %w/w.
  • Example 12- 16 were prepared and compared to the compositions according to the invention, Example 10-11.
  • the relative proportions, RP, of the carrier components sphingolipid/MCT oil/ethanol are given for each composition in % w/w.
  • CMH monohexosylceramide
  • CDH dihexosylceramide
  • LipidTeknik AB LipidTeknik AB
  • m-SL milk sphingolipids containing approximately 70 % sphingomyelin, 10 % CMH and 10 % CDH, prepared from whey concentrate by means of chromatographic fractionation (Scotia
  • Sphingomyelin prepared from whey concentrate by means of chromatographic fractionation to a purity of >99 % (Scotia LipidTeknik AB) ;
  • Glucosylceramide C8 : 0 (glucosylceramide with a C8 : 0 acyl chain linked to the amide nitrogen) from Avanti Polar Lipids, Inc.,
  • Ceramide C24 0 (ceramide with a C24:0 acyl chain linked to the amide nitrogen) from Avanti Polar Lipids, Inc., USA.
  • RP oil phase CMH/MCT oil : 3.0/97.0 %w/w, w/o : 32.9/67.1 %w/w.
  • 0.0840 g sphingomyelin was mixed with 2.4467 g MCT oil and 0.2.796 g ethanol in a sealed 10 ml glass vial. The mixture was stirred at 80 °C for 10 minutes to form a homogeneous clear oil phase . When brought back to room temperature an inhomo- geneous milky oil phase of sphingomyelin sediment in MCT oil was formed.- After the oil phase had attained room temperature, 1.3840 g of distilled water was weighed into the glass vial. The mixture was then shaken vigorously at room temperature on a vortex apparatus, with a magnetic stirring bar included in the glass vial. The result was a two. phase system consisting of one oil phase and one aqueous phase. RP oil phase; sphingomyelin/MCT oil/ethanol : 3.0/87.1/9.9 %w/w, w/o : 33.0/67.0 %w/w.
  • glucosylceramide C8 0 was mixed with 0.8140 g MCT oil and 0.0917 g ethanol in a sealed 10 ml glass vial. The mixture was stirred at 80 °C for 10 minutes to form the oil phase . When brought back to room temperature an inhomogeneous grainy oil phase was formed. After the oil phase had attained room temperature, 0.4933 g of distilled water was weighed into the glass vial . The mixture was then shaken vigorously at room temperature on a vortex apparatus, with a magnetic stirring bar included in the glass vial. The result was an inhomogeneous milky, grainy mixture of oil and aqueous phases. RP oil phase; glucosylceramide C8:0/MCT oil/ethanol : 3.0/87.2/9.8 %w/w, w/o : 34.6/65.4 %w/w.
  • ceramide C24 0.0315 g ceramide C24 : 0 was mixed with 0.9210 g MCT oil and 0.1044 g ethanol in a sealed 10 ml glass vial. The mixture was stirred at 80 °C for 10 minutes to form the oil phase. When brought back to room temperature an inhomogeneous grainy oil phase was formed. After the oil phase had attained room temperature, 0.5275 g of distilled water was weighed into the glass vial . The mixture was then shaken vigorously at room temperature on a vortex apparatus, with a magnetic stirring bar included in the glass vial . The result was an inhomogeneous mixture of oil and aqueous phases. RP oil phase; ceramide C24:0/MCT oil/ethanol : 3.0/87.1/9.9 %w/w, w/o : 33.3/66.7 %w/w.
  • Examples of pharmaceutical formulations demonstrate the ability of the carrier to incorporate bioactive substances.
  • the examples also demonstrate the versatile ways of incorporating a bioactive substance; by dissolving the bioactive substance in the aqueous phase, by dissolving the bioactive substance in the oil phase or by disperse, suspend, the bioactive substance in the carrier.
  • the procedure for preparing the different formulations was the same in Example 17-25, where the bioactive substance was dissolved in the aqueous phase.
  • Monoglycosylceramide, oil and ethanol were mixed in a sealed 10 ml glass vial and stirred at 80 °C for 10 minutes to form a homogeneous oil phase. When brought back to room temperature a macroscopically homogeneous, turbid oil phase of semi-solid consistency was formed.
  • the aqueous phase was weighed into the glass vial. The mixture was then shaken vigo- rously at room temperature on a vortex apparatus, with a magnetic stirring bar included in the glass vial . The resulting emulsion was in all examples a macroscopically homogeneous w/o- emulsion of cream-like consistency.
  • the relative proportions of the oil phase components (RP oil phase) and the ratio aqueous phase/oil phase (w/o) as well as the total concentration of bioactive substance are given in all examples .
  • monoglycosylceramide was used monohexosylceramide, CMH, prepared from whey concentrate by means of chromatographic fractionation to a purity of >96 % from Ontario LipidTeknik AB,
  • MCT oil (medium chain triglyceride oil) from Croda
  • Glycerol (99.8 %) from Apoteksbolaget AB, Sweden.
  • pH 3 buffer 50 ml 0.10 M potassium hydrogen phthalate
  • Aminolevulinic acid hydrochloride [5451-09-2] from Sigma- Aldrich;
  • vitamin C Ascorbic acid (vitamin C) [50-81-7] from Sigma-Aldrich;
  • Vancomycin hydrochloride [1404-93-9] from Sigma-Aldrich;
  • Example 18 Ascorbic acid dissolved in the aqueous phase 0.0735 g CMH was mixed with 1.2551 g MCT oil and 0.1495 g ethanol to form the oil phase. 0.9903 g of a 10.0 %w/w ascorbic acid aqueous solution was added to the oil phase .
  • Total concentration of ascorbic acid 4.0 %w/w.
  • Example 19 Aspartame dissolved in the aqueous phase
  • Example 20 Pyridoxine hydrochloride dissolved in the aqueous phase 0.0457 g CMH was mixed with 0.0117 g cholesterol, 0.9805 g MCT oil and 0.1127 g ethanol to form the oil phase. 0.8001 g of a 10.0 %w/w pyridoxine hydrochloride aqueous solution was added to the oil phase.
  • Total concentration of pyridoxine hydrochloride 4.1 %w/w.
  • Example 21 Tinzaparin sodium dissolved in the aqueous phase
  • Example 23 Vancomycin hydrochloride dissolved in the aqueous phase 0.0600 g CMH was mixed with 1.0181 g MCT oil and 0.1208 g ethanol to form the oil phase. 1.2129 g of a 10.0 %w/w vancomycin hydrochloride aqueous solution was added to the oil phase.
  • Total concentration of vancomycin hydro- chloride 5.0 %w/w.
  • Example 24 Calcium lactate dissolved in the aqueous phase
  • Example 25 Buspirone hydrochloride dissolved in the aqueous phase
  • 0.0960 g CMH was mixed with 1.5350 g MCT oil, 0.1938 g ethanol and 0.0960 g cyclosporin in a sealed 10 ml glass vial.
  • the mixture was stirred at 80 °C for 10 minutes to form a homogeneous oil phase.
  • a macroscopically homogeneous, turbid oil phase of semi-solid consistency was formed.
  • the oil phase had attained room temperature, 1.2747 g of a 5.0 %w/w NaCl aqueous solution, the aqueous phase, was weighed into the glass vial.
  • 0.0368 g CMH was mixed with 0.9401 g MCT oil, 0.1250 g ethanol, 0.1250 g glycerol and 0.8037 g metronidazole benzoate in a sealed 10 ml glass vial.
  • the mixture was stirred at 80 °C for 10 minutes to form a homogeneous oil phase.
  • a macroscopically homogeneous, turbid oil phase of semi-solid consistency was formed.
  • the aqueous phase was weighed into the glass vial. The mixture was then shaken vigorously at room.
  • the ability of the carrier of the present invention to form macroscopically homogeneous w/o-emulsions of cream-like consistency even when the aqueous phase has a considerable high ionic strength or has a pH value far from neutral pH, is demonstrated in the following examples.
  • the procedure for preparing the different compositions was the same in all examples. Monoglycosylceramide, oil and ethanol, the same as in the previous examples, were mixed in a sealed 10 ml glass vial and stirred at 80 °C for 10 minutes to form a homogeneous oil phase. When brought back to room temperature a macroscopically homogeneous, turbid oil phase of semi-solid consistency was formed.
  • the aqueous phase was weighed into the glass vial. The mixture was then shaken vigorously at room temperature on a vortex apparatus, with a magnetic stirring bar included in the glass vial. The resulting emulsion was in all examples a macroscopically homogeneous w/o- emulsion of cream-like consistency.
  • Example 17 To demonstrate the ability of the w/o-emulsion carrier of the present invention to incorporate substances, which demand extreme pH values to retain stable, the stability of aminolevulinic acid was examined by means of high performance liquid chromatography.
  • the pharmaceutical formulation of Example 17 was stored at room temperature for approximately 3 months, protected from light, before the analysis was made.
  • Example 17 Approximately 200 mg of the pharmaceutical formulation of Example 17 was accurately weighed and dissolved in 4 ml hexane/isopropanol : 4/1 by volume in a test tube, 2 ml distilled water was added and the mixture was vigorously shaken and slightly heated for 10 to 20 seconds in a water bath at 50 °C. After centrifugation at 3500 rpm for 1 min the upper organic layer was discarded and the water phase was washed twice more with 4 ml of the hexane/isopropanol mixture. The resulting water phase was diluted up to 10 ml with the mobile phase and injected on the chromatographic system described above . The aminolevulinic acid concentration in the samples was evaluated by means of a three point standard curve (1-3 mg/ml) . The sample was prepared in duplicate. The analysis showed a 92 and 94 % recovery of aminolevulinic acid, respectively.
  • sustained release properties of w/o-emulsion systems of the present invention are illustrated by the incorporation and release of three different marker substances, Safranine O, pyridoxine hydrochloride and ascorbic acid.
  • monoglycosylceramide was used monohexosylceramide, CMH, prepared from whey concentrate by means of chromatographic fractionation to a purity of >96 % from Ontario LipidTeknik AB, Sweden.
  • MCT oil (medium chain triglyceride oil) from Croda Oleochemicals, England. Sesame oil from Croda Oleochemicals, England.
  • vitamin C Ascorbic acid (vitamin C) [50-81-7] from Sigma-Aldrich.
  • a conventional USP dissolution bath, PTWS has been modified so that it can be used with smaller volumes.
  • the lids to the original vessels have been modified so a 50 ml round bottomed flask can be placed in them.
  • the original paddles were made smaller to fit into these new vessels, which hang inside the original vessels, which were filled with water.
  • the tempera- ture in the water bath was set to 38.1 °C, which corresponds to a temperature of 37.2-37.3 °C inside the 50 ml vessel.
  • the oil phase was prepared by mixing monoglycosylceramide, cholesterol (when included) , non- polar oil and ethanol in a sealed 10 ml glass vial. The mixture was stirred at 80 °C for 10 minutes to form a homogeneous oil phase. After the oil phase had attained room temperature and become turbid, macroscopically homogeneous and of semi-solid consistency, the aqueous phase with the dissolved marker substance was weighed into the glass vial . The mixture was then shaken vigorously at room temperature on a vortex apparatus, with a magnetic stirring bar included in the glass vial, to form a macroscopically homogeneous w/o-emulsion of cream-like consistency. The w/o-emulsion was finally transferred to 2 ml syringes to ease the filling of the Spectra/Por ® Membrane. The composition of the formulations examined is given in Table 1 and Table 2.
  • Membrane and the membrane was locked at both ends with weighted closures .
  • the formulation in its membrane was put in the medium and samples were taken after specific times.
  • the dissolution medium was used as a blank on the UV spectrophotometer.
  • the peristaltic pump which is adherent to the flow cuvette system of the UV-spectrophotometer, was used.
  • the flow cuvette was filled with sample and the absorbance was measured at 521 nm (Saf O) , 324 nm (pyridoxine hydrochloride) and 265-290 nm (ascorbic acid) .
  • the pump was allowed to work in the reverse direction and the sample was returned to the inner vessel .
  • the cuvette system was finally rinsed thoroughly with dissolution medium. Results from the release studies
  • Examples 17-27 in which about 0.5-32 % by weight of eleven structurally very different bioactive substances successfully have been incorporated.
  • the characteristics of the w/o-emulsion carrier composition of the invention make it especially suitable as a pharmaceutical carrier for controlled release of incorporated bioactive substances.
  • the compositions of the oil phase and the aqueous phase, and the ratio aqueous phase/oil phase of the w/o-emulsion carrier composition can be adjusted to facilitate the incorporation and protection of various bioactive substances, and to control the release rate from the carrier.

Abstract

L'invention concerne une composition support d'émulsion eau dans huile permettant la libération contrôlée d'une substance bioactive. Cette composition support contient une phase huileuse d'au moins une huile non-polaire, un monoglycosylcéramide et éventuellement un éthanol, et une phase aqueuse dispersée dans cette phase huileuse. Cette composition support est apte à former une structure cohésive qui est retenue dans un environnement aqueux. L'invention concerne également une formulation pharmaceutique destinée à une libération contrôlée d'une substance bioactive et composée d'une composition support d'émulsion eau dans huile et d'une substance bioactive dissoute ou dispersée dans cette composition support.
PCT/SE2002/001572 2001-09-04 2002-09-03 Composition support d'emulsion eau dans huile WO2003020319A1 (fr)

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SE0102933A SE0102933D0 (sv) 2001-09-04 2001-09-04 Lipid carrier

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014063985A3 (fr) * 2012-10-25 2014-07-31 Nestec S.A. Peptides amers encapsulés, procédés d'encapsulation de peptides amers, et compositions nutritionnelles comprenant des peptides amers encapsulés
WO2016081478A1 (fr) * 2014-11-18 2016-05-26 Gary Hall Compositions à base d'huile pour améliorer la santé buccale et le bien-être général d'êtres humains
US11109607B2 (en) 2013-11-18 2021-09-07 Gary Hall Oil-based compositions for enhancing oral health and general wellness in humans

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US4610868A (en) * 1984-03-20 1986-09-09 The Liposome Company, Inc. Lipid matrix carriers for use in drug delivery systems
US5912271A (en) * 1994-07-12 1999-06-15 Astra Ab Pharmaceutical preparation for pain management
JP2000119178A (ja) * 1998-10-13 2000-04-25 Shionogi & Co Ltd セラミド含有組成物
WO2001066086A1 (fr) * 2000-03-06 2001-09-13 Lipocore Holding Ab Excipient liquide

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US4610868A (en) * 1984-03-20 1986-09-09 The Liposome Company, Inc. Lipid matrix carriers for use in drug delivery systems
US5912271A (en) * 1994-07-12 1999-06-15 Astra Ab Pharmaceutical preparation for pain management
JP2000119178A (ja) * 1998-10-13 2000-04-25 Shionogi & Co Ltd セラミド含有組成物
WO2001066086A1 (fr) * 2000-03-06 2001-09-13 Lipocore Holding Ab Excipient liquide

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DATABASE WPI Week 200031, Derwent World Patents Index; Class D21, AN 2000-359603, XP002958492 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014063985A3 (fr) * 2012-10-25 2014-07-31 Nestec S.A. Peptides amers encapsulés, procédés d'encapsulation de peptides amers, et compositions nutritionnelles comprenant des peptides amers encapsulés
AU2013336907B2 (en) * 2012-10-25 2017-06-15 Société des Produits Nestlé S.A. Encapsulated bitter peptides, methods of encapsulating bitter peptides, and nutritional compositions including encapsulated bitter peptides
US11109607B2 (en) 2013-11-18 2021-09-07 Gary Hall Oil-based compositions for enhancing oral health and general wellness in humans
WO2016081478A1 (fr) * 2014-11-18 2016-05-26 Gary Hall Compositions à base d'huile pour améliorer la santé buccale et le bien-être général d'êtres humains

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