Classifications

• • 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
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/55—Linaceae (Flax family), e.g. Linum
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
• • 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
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • 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

Definitions

• linseed mucilage is a viscous liquid obtained by an aqueous extraction of the seeds of the linseed plant. Linseed mucilage acts as a bulking agent and is used in the treatment of constipation. Linseed mucilage is
• sucralfate sulphated sucrose and aluminium hydroxide
• bioadhesive materials have utility as muco-adherents and may be used by themselves or in
• linseed mucilage has bioadhesive properties which confer practical utility when the material is applied to the skin and mucous membrances of the body, both in isolation and in combination with other active treating substances. Tests have shown a positive mucus- mucilage interaction.
• composition of matter comprising linseed mucilage for the manufacture of a medicament for topical application to the skin and/or mucous
• the invention provides the use of a composition of matter comprising linseed mucilage as a cosmetic preparation for topical application to the skin and/or mucous membranes of the human body.
• a composition of matter comprising linseed mucilage as a cosmetic preparation for topical application to the skin and/or mucous membranes of the human body.
• linseed mucilage as a mucosal or mucous-adherent are included its use as an artificial mucus and/or lubricant for application to the skin surface, the occular, nasal, oral, vaginal and anal cavities; its use as a mucoadherent in the
• linseed mucilage As a cytoprotective agent, linseed mucilage has been shown to compare favourably with other muco-adherents, for example sucralfate, in
• topical application is not limited to application to the skin and/or exposed mucous surfaces of the body but rather includes any such surface, whether internal or external.
• composition of matter comprising linseed mucilage in combination with an active treating substance has utility as a delivery system for effecting localised and/or controlled release of the active treating substance.
• Such combinations for example when administered orally, have moreover a cytoprotective effect and are useful in preventing or mitigating damage induced by said active treating substances.
• the present invention provides a composition of matter comprising linseed mucilage in combination with an active treating substance.
• a method of controlled release treatment also constitutes an aspect of the invention.
• active treating substance includes medicaments, cosmetic substances and nutritional agents.
• Cosmetic substances as referred to herein include sun-screening agents, skin treatments such as skin softeners and anti-acne agents, perfumes and the like.
• Nutritional substances as referred to herein include vitamins and minerals.
• medicament as used herein refers to any therapeutic substance, suitably any therapeutic substance that is effective via
• combination of an active therapeutic substance with linseed mucilage can confer not only controlled release of the substance but, in addition, depending on the nature and purpose of the substance, retention of the substance at the target site promoting, inter alia, a localised effect at the target site, or, for substances which are absorbed either
• An active treating substance as used in compositions of the present invention may be used singly or in combination with one or more other active treating substances.
• An active treating substance more particularly an active treating substance which is a medicament, will be present in the composition in an amount that is sufficient to prevent, cure and/or alleviate the condition requiring treatment. Such an amount is referred to hereinafter as an effective amount of the active treating substance.
• the effective amount of a given active treating substance is dependent on the substance, for example its physico-chemical properties such as molecular weight and charge, the condition requiring treatment and the manner of administration. Such amounts may be determined by methods known in the art of biophysical chemistry.
• Linseed mucilage for use in the present invention may be in the form of a viscous liquid, the viscosity of which may be selected to suit for example mode and/or site of administration.
• liquid linseed mucilage preparations may be administered as a mouth rinse, wash or spray for retention in the oral cavity or as a liquid
• linseed mucilage may be in a dried form for reconstitution with water prior to use, or for reconstitution on contact with body fluids at a mucous surface of the body.
• Linseed mucilage and purified forms thereof may for example be dried to form a powder or alternatively, cast as a thin film which on rehydration adheres to the surface of the skin or mucuous membrane to which it is applied.
• Linseed mucilage for use in the invention may be incorporated in a range of product presentations for oral delivery, including pastes and gelled products, such as gums, for example a chewing gum, and lozenge
• Presentations for oral delivery may be formulated for retention in the mouth, for example to be sucked, chewed or applied to the teeth or gums, or as presentations intended for swallowing.
• an active treating substance is combined with linseed mucilage and is intended to treat or prevent disorders associated with the oral cavity
• the product is suitably formulated for retention in the mouth.
• the active treating substance is intended to treat or prevent disorders requiring absorption of the substance from the gastrointestinal tract
• the product may be formulated either for release of the active substance in the mouth or preferably a swallow product.
• Processes for preparing raw linseed mucilage, dried forms thereof and gels, for example gum, lozenge and thin film formulations are a feature of the present invention.
• Raw linseed mucilage may for example be obtained as a viscous, pseudoplastic liquid by boiling linseed in water, suitably for 2 to 10 minutes, favourably for 3 to 5 minutes, and filtering the product.
• linseed mucilage having a dry weight of 1.0 to 1.6g per 100ml is obtained -from an extraction of 1 part linseed to 10 parts water under these conditions.
• the seeds may be cracked prior to processing but use of whole, intact seed is generally preferred.
• linseed mucilage may be prepared from separated seed-coats. Percentage dry weight is dependent on a number of variables including for example seed-type and the extraction conditions employed for isolating the mucilage.
• linseed mucilage may also be obtained by aqueous extraction over a range of temperatures, for example at room temperature in which case the extraction process may extend over several hours.
• Mucilage obtained by extraction at or around room temperature generally has a lower percentage dry weight than material obtained by extraction at elevated temperature.
• the liquid product may be dried using state of the art drying techniques, for example oven-, freeze- and spray-drying techniques, preferably an oven-drying or freeze-drying technique.
• the native properties of the raw mucilage can be retained by combining it with gelling agents.
• Such agents would typically be gelatin, natural or synthetic gums.
• the gelation of the mucilage results in a retention of the native structure and the reconstitution upon dissolution of the gel matrix.
• the finished product may resemble dosage forms ranging from soft gels to hard lozenges.
• the rheological properties, for example the pseudoplastic and bioadhesive properties of the raw mucilage are retained on rehydration of dried mucilage, more especially when the dried mucilage is prepared by oven-drying.
• the raw mucilage is suitably maintained at a temperature of about 60°C.
• Purified forms of linseed mucilage also form part of the present invention. Dialysis of the mucilage against aqueous solutions removes low molecular weight materials that contribute to the odour and appearance of the mucilage. The dialysis of the mucilage against compositions of choice can be used in order to incorporate other components of formulations.
• Raw mucilage may be subjected to ultrafiltration, to provide a high molecular weight mucilage fraction. Ultrafiltration, for example against a 10,000 molecular weight cut-off membrane against water, may be carried out prior to drying or gelling the raw linseed mucilage. Linseed mucilage which has been subjected to ultrafiltration retains the physical properties of raw mucilage. Morever, when raw mucilage is subjected to
• a further purified form a linseed mucilage is obtainable by treating raw linseed mucilage with a low molecular weight, water-soluble alcohol, for example a C 1-6 alkyl alcohol, such as ethanol or isopropanol. Treatment with the alcohol causes precipitation of a component of the raw mucilage which may be isolated as a fibrous solid.
• a low molecular weight, water-soluble alcohol for example a C 1-6 alkyl alcohol, such as ethanol or isopropanol. Treatment with the alcohol causes precipitation of a component of the raw mucilage which may be isolated as a fibrous solid.
• the alcohol precipitated material has similar rheological characteristics to the raw mucilage when it is reconstituted into aqueous solutions.
• the precipitate and he reconstituted material lack the characteristic odour and colour of linseed mucilage.
• the reconstituted material is less subject to degradation than the raw material.
• Alcohol precipitated linseed mucilage is accordingly a preferred form of mucilage according to the present invention.
• the alcohol precipitated material in common with raw mucilage, has been shown by chemical characterisation to consist of proteinaceous, saccharide and oil components in covalent or intimate admixture.
• a typical mucilage preparation may contain up to 15% w/w of protein, up to 98% w/w of saccharides and up to 10% w/w of oils.
• the composition of a typical alcohol precipitated material is given in Example 4.
• the present invention also provides linseed mucila and a method of preparation hereo herein the rheological properues, for example the viscosity of the mucilage in hydrated form, may be controlled to suit a chosen utility. It has for example been found that there is a marked difference in rheological behaviour between mucilage preparations, dependent on the amount of linseed used to prepare the raw mucilage. It has moreover been found that dilution of a concentrated or highly viscous mucilage preparation does not generate a homogenous mucilage preparation having reduced viscosity.
• the viscosity of such linseed mucilage preparations is rather controlled by varying the quantity of linseed present in the mixture of linseed and water during initial processing.
• the ability to reduce viscosity by dilution is a feature of mucilage preparations of low percentage dry weight which are formed initially as free-flowing viscous liquids. This supports the view that the rheology of linseed mucilage is at least partially determined by a concentration dependent polymeric entanglement.
• the rheology of linseed mucilage preparations is also dependent on the linseed variety used to prepare the mucilage. It has been found for example that by subjecting a given amount of different seed types to identical extraction processes, mucilages having a range of viscosities can be obtained.
• rheology is dependent on the conditions under which the mucilage is extracted from the linseed. It has been shown that the viscosity of mucilage obtained by aqueous extraction is dependent on temperature, low temperature extraction generally giving rise to less viscous material than extraction at elevated temperature, for example by extraction with boiling water. Differences in rheology may be attributed, at least in part, to the molecular weight of the mucilage extract, extraction at elevated temperature giving rise to a higher proportion of high molecular weight materials.
• a 1.2% dry weight mucilage will have an initial viscosity in the range 100 to 200cps.
• the viscosity of linseed mucilage may therefore be selected to
• the mucilage may range from a mobile liquid (eg. 5 to 50 cps, suitably 30 or 35 to 50cps), through a thick but nevertheless pourable liquid (eg. 50 to 300 cps, suitably 80 to 150cps) to a gellatinous
• a mobile liquid eg. 5 to 50 cps, suitably 30 or 35 to 50cps
• a thick but nevertheless pourable liquid eg. 50 to 300 cps, suitably 80 to 150cps
• composition (eg. greater than 300cps).
• linseed mucilage renders it of utility as a viscosity controlling agent in liquid preparations, for example in liquid preparations for oral consumption.
• linseed mucilage may be used as a sugar substitute in liquid syrups.
• linseed mucilage as a viscosity controlling agent forms an aspect of the present invention.
• a yet further potential benefit of linseed mucilage for topical application to the human or animal body is derived from the effect of proteolytic enzymes on the rheological properties of the mucilage. It has been found that the viscosity of a mucilage preparation is reduced as a function of time in the presence of proteolytic enzymes. It will be appreciated that proteolytic degradation can be used to advantage in applications according to the invention, for example when linseed mucilage is used as a drug delivery system. Particularly suitable applications include linseed mucilage incorporating an active treating substance for delivery to the occular, nasal or vaginal cavities of the body.
• compositions for use in the present invention may include
• compositions according to the invention are substantially non-toxic to humans and animals, discounting any toxicity which may be associated with incorporation of an active treating
• the amount of active treating substance or effective amount of the active treating substance will be an amount that is not expected to confer any unacceptable toxicological effects.
• Novel linseed mucilage formulations as hereinbefore described form part of the present invention as do their use as novel therapeutic agents, including their use in the treatment of gastric disorders.
• Linseed mucilage preparations according to the present invention together with data illustrating their rheological properties are described in the following Examples. Linseed mucilage preparations according to the present invention may be prepared from any linseed variety.
• the resulting mucilage was a viscous pseudoplastic liquid, pale golden in colour.
• the mucilage was found to have a dry weight of 1.1 to 1.3g per 100ml.
• the material was stored at 4°C to avoid bacterial spoilage.
• the frozen sample was subjected to freeze-drying in a freeze drier.
• the isolated, freeze-dried mucilage was a fibrous, low- density pale yellow powder.
• Raw linseed mucilage as prepared in Example 1 was treated with an equal volume of isopropyl alcohol. This treatment precipitated out approximately 80% of the dry weight of the mucilage comprising the protein, saccharide and some residual oil component of the raw mucilage.
• the initial precipitate was a white, odourless, fibrous material which rehydrated to a mucilage-like material on exposure to air .
• a typical mucilage preparation would have the following characteristics: a)
• Such components may exist as admixtures, intimate mixes or covalent structures such as a glycoprotein or glycolipid.
• Nitrogen conversion factor 5.88 (calculated from amino acid data)
• Viscosity (Brookfield Viscometer) Viscosity may range from: 5 to 5000 cps f) Action of Proteolytic Enzyme
• test material approximately 100mg.
• test material approximately 10ml.
• distilled water approximately 10ml.
• Hydrochloric acid 0.1M Hydrochloric acid
• Freeze dried Mucilage - freeze dried powders proved difficult to wet, the material attaining a 'swollen volume' with time. The time taken to reach this final swollen volume was measureable in days. Hot and boiling water produced very similar results. The material rehydrated in acid appeared slightly less viscous.
• Spray dried Mucilage - The rehydration of the material was examined in both water and O.IM hydrochloric acid. The spray dried material formed a swollen mass in both environments, this slowly dispersed over several days to form a dark brown liquid/suspension. The material in 0.1M acid appeared to be slightly less viscous than that in water. The addition of boiling water to the spray dried mucilage appeared to have no effect upon the rehydration. Freeze dried ultrafiltrated Mucilage - this material appeared to behave in a manner identical to that seen in the freeze dried material. There was some evidence that the pseudoplasticity of the material had been reduced by the shear forces generated by the stirring within the untrafiltration cell.
• the resuspensions were graded as follows in order of appearance
• Mucoadhesion Assay A comparison of the mucoadhesion of the dried forms of linseed mucilage was made using a method based upon a tensiometer study of adherence to porcine gastric mucous. The adhesive properties of raw linseed mucilage were also compared to those shown by porcine stomach mucous. The dried mucilage and the raw mucilage experiments included a negative control
• PAA Polyacrylic acid
• SDLM Spray-dried Linseed Mucilage
• FDLM Freeze-dried linseed Mucilage
• Table 1 shows the results obtained for the detachment weights of the investigative materials from mucous, expressed as a percentage of the control.
• Table 1 Detachment weight of variousommeg ative polymeric ext racts from mucous (expressed as a percentage of the control )
• Table 2 shows the corresponding detachment values which were obtained when polyacrylic acid (PAA) and acacia were detached from raw linseed mucilage in place of mucous.
• PAA polyacrylic acid
• Table 2 Mean Detachment weight (expressed as a percentage of the control) of Polyacrylic acid (PAA) and acacia from freshly constituted linseed mucilage, employing a contact time between polymer and mucilage of 5 minutes
• Example 8 The resulting gels, on treatment with hot water, rehydrated to provide a colourless, odourless mucilage.
• Example 10 The resulting gels, on treatment with hot water, rehydrated to provide a colourless, odourless mucilage.
• Drug-mucilage complexes were prepared from linseed mucilage and each of the following compounds: dyclonine, phenylephrine, lignocaine, cimetidine, loperamide, cetyl pyridinium choride (CPC) and chlorhexidine.
• the complexes were prepared by adding a known quantity of an aqueous solution of the drug to a known volume of linseed mucilage prepared as per Example 1. On mixing mucilage with CPC and chlorhexidine, the complex formed as a fiocculant precipitate which was separated from the aqueous supernatant by centrifugation, washed with water and filtered.
• the drug content of these two complexes was determined by HPLC analysis of dried samples.

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Citations (5)

• 1992
  • 1992-02-19 GB GB929203474A patent/GB9203474D0/en active Pending
• 1993
  • 1993-02-18 AU AU35094/93A patent/AU3509493A/en not_active Abandoned
  • 1993-02-18 WO PCT/GB1993/000343 patent/WO1993016707A1/en not_active Application Discontinuation
  • 1993-02-18 EP EP93904227A patent/EP0674522A1/en not_active Withdrawn
  • 1993-02-18 JP JP5514630A patent/JPH07504182A/ja active Pending
  • 1993-02-18 CA CA002130350A patent/CA2130350A1/en not_active Abandoned

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