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WO2006079830A1 - Composes - Google Patents

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Publication number
WO2006079830A1
WO2006079830A1 PCT/GB2006/000290 GB2006000290W WO2006079830A1 WO 2006079830 A1 WO2006079830 A1 WO 2006079830A1 GB 2006000290 W GB2006000290 W GB 2006000290W WO 2006079830 A1 WO2006079830 A1 WO 2006079830A1
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WO
WIPO (PCT)
Prior art keywords
lanolin
derivative
peg
ppg
rtm
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/GB2006/000290
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English (en)
Inventor
Ian Steel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Croda International PLC
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Croda International PLC
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Filing date
Publication date
Priority claimed from GB0501861A external-priority patent/GB0501861D0/en
Priority claimed from GB0501857A external-priority patent/GB0501857D0/en
Application filed by Croda International PLC filed Critical Croda International PLC
Publication of WO2006079830A1 publication Critical patent/WO2006079830A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/10—Saturated ethers of polyhydroxy compounds
    • C07C43/11—Polyethers containing —O—(C—C—O—)n units with ≤ 2 n≤ 10
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
    • C11C3/00—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/75—Anti-irritant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings

Definitions

  • the present invention relates to antipruritic compositions comprising alkoxylated and in particular ethoxylated lanolin and/or alkoxylated and in particular ethoxyiated lanolin derivatives as the antipruritic agent, and to methods of manufacturing such compositions.
  • the invention further relates to the use of these compositions for treating parts of the mammalian body, particularly the skin.
  • Lanolin wool wax
  • lanolin is the naturally occurring protective lipid found on the wool of sheep. Chemically, lanolin is a complex mixture of waxy esters, alcohols, acids and hydrocarbons. Lanolin has been shown to possess a high degree of similarity to human stratum corneum lipids, the lipids responsible for controlling trans-epidermal water loss (TEWL) and subsequent skin hydration levels.
  • TEWL trans-epidermal water loss
  • Wool wax is a true wax in the chemical sense, there being no glycerides present, but rather it comprises a highly complex mixture of esters of fatty alcohols with fatty acids, both of which are of several different types and covering a wide range of molecular weight.
  • a typical composition of pharmaceutical grade lanolin comprises, by weight:
  • lanolin alcohols the unsaponifiable fraction of lanolin
  • lanolin oil the liquid ester fraction of lanolin
  • Lanolin is known to possess excellent emollient properties, which has resulted in its widespread inclusion in topical products over many years. In addition to this use, a large quantity of lanolin produced worldwide each year is used as a starting material for the production of lanolin derivatives.
  • lanolin and certain lanolin derivatives, as examples of lipid materials are well known for their unique blend of emollient, moisture retentive and skin penetrating properties, particularly in compositions such as cosmetics and medicaments for treatment of the skin and other parts of the body.
  • the chemical constitution of lanolin and its useful properties are discussed for example in European Patent Application EP-A-0602961.
  • lanolin-containing compositions in the form of oil-in-water emulsions for cosmetic and other applications are disclosed for instance in GB-A-1530064 and US-A-3666857.
  • the text of these three patent documents are hereby incorporated by reference and are intended to form an integral part of he present disclosure.
  • Lanolin like many other lipids, can be rendered water-soluble / dispersible by ethoxylation and alcohol soluble / dispersible by propoxylation.
  • Lanolin ethoxylates may be prepared by reacting lanolin (or a suitable lanolin derivative) with gaseous ethylene oxide (under alkaline conditions) to form the corresponding polyoxyethylene derivative. Similar reaction conditions are used in the manufacture of lanolin propoxylates. Other known methods of manufacture of ethoxylates include the direct condensation of the lipid with a polyethylene glycol chain of suitable chain length.
  • Ethoxylated lanolin derivatives are well known for their non-ionic emulsifying, solubilising and foam boosting properties, which makes them ideal for use in topical skin care formulations such as creams, lotions, shampoos and conditioners etc. To date, however, there has been no suggestion that such derivatives, particularly the 9- mole ethoxylated derivatives, would exert anti-pruritic effects.
  • Itch is a widespread and complex phenomenon. Itch is a major symptom of many dermatological conditions, for example, atopic eczema, urticaria, xerosis, senile pruritus etc. In addition to the incidence, prevalence and frequency of itch in 'compromised' skin conditions such as atopic dermatitis, itch is also often prevalent in apparently healthy skin, for example, the itch associated with sunburn or after contact with water (aquagenic pruritus). A wide array of mediators has thus far been identified or implicated in the transmission of itch, for example histamine, prostaglandins, substance P, other peptides and proteins etc.
  • compositions have been reported to relieve itching. These include those compositions described in US4, 797,402 (Dorsey) containing a mixture of corticosteroid, peppermint oil and urea, those in US5,961 ,997 (Swinehart) containing a mixture of camphor, menthol and phenol, and those in US6,248,763 (Scivoletto) containing nicotinic acid derivatives.
  • Such mixtures may be lanolin-free or may contain lanolin or lanolin-derived materials but it is clear in the context of those disclosures that any lanolin component is included for its properties as an emollient or surfactant, not because it reduces itch per se.
  • lanolin derivatives in topical formulations include
  • Lohmann Therapie-Systeme GmbH describes formulations which are designed to increase the transdermal permeation of biolofically active substances. Whilst these formulations contain polyethyleneglycol ethers of lanolin derivatives, none of these derivatives are of lanolin itself. And there is no mention that the formulations may be useful in itch.
  • Emulsifiers for cosmetic purposes are described in US4,600,539 (Briersdorf). In this case wool wax acid glycerol esters are subjected to ethoxylation, rather than lanolin itself.
  • Surfactants comprising ethoxylated lanolin have been used from time to time in anti-itch preparations such as in US4, 797,402 (Dorsey).
  • the anti-itch component is a non-lanolin derived compound such as a corticosteroid, peppermint oil or urea.
  • the aim of this invention is to combine the beneficial lipid properties of lanolin and/or one of its many derivatives such as lanolin alcohols, lanolin acids, hydrogenated lanolin etc with polyethers such as 9-moles of polyethylene glycol (PEG) to produce hitherto unknown compounds possessing anti-pruritic activity.
  • lanolin and/or one of its many derivatives such as lanolin alcohols, lanolin acids, hydrogenated lanolin etc
  • polyethers such as 9-moles of polyethylene glycol (PEG)
  • a high-purity grade of lanolin clinically proven to be hypoallergenic and acceptable for use on compromised skin conditions, is preferred as a starting material, for example, one chosen from the MedilanTM range (Croda Chemicals Europe Ltd) but lanolin alcohols, lanolin acids, hydrogenated lanolin, may also be used as a starting material.
  • compositions of the invention may also find use in other industrial, agricultural, veterinary and/or domestic applications.
  • Wool wax or purified lanolin lanolin purified to varying levels of removed impurities such as allergens and pesticides
  • Such lanolin for use in the invention may be hydrous or, more preferably, anhydrous.
  • Physically or chemically obtained lanolin derivatives suitable for use as starting materials in the present invention may include for example lanolin oil, lanolin alcohols, lanolin esters (eg isopropyl lanolate) and hydrogenated lanolin. Suitable examples of these lanolin and lanolin-derived materials are readily available commercially and their derivation and/or preparation is widely documented in the patent and technical literature.
  • novel antipruritic agents comprising a PEG-9 or PPG-9 lanolin derivative formed by derivatisation of lanolin or a lanolin derivative with 9 molar equivalents of ethylene oxide or propylene oxide respectively or with the equivalent polyethylene glycol or polypropylene glycol.
  • the lanolin component comprises MEDILAN (RTM).
  • the lanolin component comprises lanolin alcohols and in particular SUPER HARTOLAN (RTM).
  • the lanolin component comprises hydrogenated lanolin, preferably SATULAN (RTM).
  • a chemical composition for treatment of itch comprising as active antipruritic agent alkoxylated lanolin or an alkoxylated lanolin derivative.
  • the active antipruritic agent comprises an ethoxylated lanolin or an ethoxyiated lanolin derivative, more preferably a PEG-# lanolin or a PEG-# derivative of a lanolin derivative wherein # is an integer between 1 and 30.
  • # is an integer between 1 and 20, and more preferably # is an integer between 1 and 15.
  • the active antipruritic agent may comprise propoxylated lanolin or a propoxylated lanolin derivative, more preferably a PPG-# lanolin or a PPG-# derivative of a lanolin derivative wherein # is an integer between 1 and 30.
  • # has the integer values described above.
  • the alkoxylated lanolin comprises a PEG-9 derivative of MEDILAN (RTM), available from Croda Health Care UK.
  • the alkoxylated lanolin derivative comprises a PEG-9 derivative of lanolin alcohols and in particular a PEG-9 derivative of SUPER HARTOLAN (RTM) available from Croda Health Care UK.
  • RTM SUPER HARTOLAN
  • the alkoxylated lanolin derivative comprises a PEG-9 derivative of hydrogenated lanolin and in particular a PEG-9 derivative of SATULAN (RTM), available from Croda Health Care UK.
  • RTM SATULAN
  • composition further comprises at least one member selected from the group consisting of:-
  • the amount of alkoxylated lanolin or alkoxylated lanolin derivative in the composition is in the range 0.05% to 40% and preferably in the range 0.5% to 15% by weight based on the total weight of the composition.
  • PPG-# lanolin derivative formed by derivatisation of lanolin or a lanolin derivative with # molar equivalents of ethylene oxide or propylene oxide respectively or the equivalent polyethylene glycol or polypropylene glycol when used as an antipruritic agent in a composition intended for application to the skin to reduce itch.
  • # is an integer between 1 and 30.
  • # is an integer between 1 and 20.
  • # is an integer between 5 and 15.
  • said lanolin component comprises MEDILAN (RTM).
  • said derivative comprises PEG-9 MEDILAN (RTM).
  • said lanolin component comprises lanolin alcohols.
  • said lanolin component comprises SUPER HARTOLAN (RTM).
  • said lanolin component comprises hydrogenated lanolin, and preferably SATULAN (RTM).
  • an alkoxylated lanolin or an alkoxylated derivative of a lanolin derivative as an antipruritic agent in the manufacture of a medicament for the treatment of itch.
  • said antipruritic agent comprises an ethoxylated lanolin or an ethoxylated lanolin derivative.
  • said antipruritic agent comprises PEG-# lanolin or a PEG-# derivative of a lanolin derivative where # is an integer between 1 and 30.
  • # is an integer between 1 and 20 and preferably # is an integer between 1 and 15.
  • the antipruritic agent comprises a PEG-9 derivative of MEDILAN (RTM).
  • the alkoxylated lanolin derivative comprises a PEG-9 derivative of lanolin alcohols and in particular a PEG-9 derivative of SUPER HARTOLAN (RTM).
  • the alkoxylated lanolin derivative comprises a PEG-9 derivative of hydrogenated lanolin, and in particular a PEG-9 derivative of SATULAN (RTM).
  • said antipruritic agent comprises a propoxylated lanolin or a propoxylated derivative of a lanolin derivative, more preferably a PPG-# lanolin or a PPG-# derivative of a lanolin derivative wherein # is an integer between 1 and 30.
  • # has the integer values described above.
  • said antipruritic agent comprises a PPG-9 derivative of MEDILAN (RTM).
  • said antipruritic agent comprises a PPG-9 derivative of lanolin alcohols, and in particular a PPG-9 derivative of SUPER HARTOLAN (RTM); or a PPG-9 derivative of hydrogenated lanolin and in particular a PPG-9 derivative of SATULAN (RTM).
  • Said medicament may further comprise at least one member selected from the group consisting of:-
  • the amount of alkoxylated lanolin or alkoxylated lanolin derivative in the composition is in the range 0.05% to 40% and preferably in the range 0.5% to 10% by weight based on the total weight of the composition.
  • alkoxylated lanolin or an alkoxylated lanolin derivative as an antipruritic agent in the treatment of itch.
  • itch is not an ailment requiring therapy.
  • the lanolin component preferably comprises a PEG-# lanolin or a
  • the antipruritic agent comprises at least one member selected from the list comprising:- (i) PEG-9 MEDILAN (RTM).
  • lanolin is a natural, animal harvested material.
  • lanolin refining neutralisation, washing, bleaching, active earth treatment
  • processes employed in conventional lanolin refining are designed to remove particulate matter, free lanolin acids, colouring species and detergent residues and are sufficient to produce a product which conforms to the requirements of the lanolin monographs to be found in pharmacopoeia.
  • lanolin is properly considered to be a wax.
  • the natural complexity of this mixture is such that the theoretical number of mono-ester combinations alone is estimated to exceed 10,000.
  • the lanolin matrix also contains di- esters, free lanolin alcohols and low levels of free lanolin acids and lanolin hydrocarbons.
  • Liquid lanolin is a physical derivative which is obtained by means of a fractional crystallisation process. As the name suggests, it is a fraction of the lanolin matrix which is liquid at typical ambient temperatures. As no chemical modification has taken place, all of the components of liquid lanolin are components of ordinary lanolin. Consequently, it retains the basic emollient and emulsification properties of lanolin but in a liquid form.
  • Lanolin Alcohols is a chemical derivative which is one of the products of the alkaline hydrolysis of lanolin. It is separated from the soaps in the resultant hydrolysate mixture by means of solvent extraction. Following removal of the solvent, the crude lanolin alcohols is molecularly distilled to yield a pale yellow product which conforms to the requirements of the PhEur monograph for "Wool Alcohols".
  • Lanolin Alcohols differs significantly from both lanolin and liquid lanolin. Physically, it is a brittle solid having a melting point of >58°C. Chemically, it is a mixture of alcohols (straight- and branched-chain aliphatics, diols, sterols and trimethylsterols) of which cholesterol predominates. As a consequence of the greatly increased number of hydroxy moieties, Lanolin Alcohols is an extremely powerful W/O emulsifier.
  • the different grades of Lanolin and Liquid Lanolin in the Croda/Westbrook range of Medical Grade Lanolins and Lanolin Derivatives are each produced by further refining the conventional material by means of one of two purification processes. Both processes produce high purity products by utilising existing, proven technology and both remove pesticide residues and other contaminants by physical means. Therefore, there is no chemical modification of the lanolin or liquid lanolin and no decomposition artefacts are introduced.
  • Molecular Distillation is a high temperature process which is conducted under vacuum and used to remove the pesticide residues from the bulk material in a relatively small distillate fraction. It can also be used to decrease the level of free lanolin alcohols in lanolin or liquid lanolin. Although the process operates at an elevated temperature there is no deleterious effect on the colour of the product because the residence time is short.
  • Chromatography can be used to improve the quality of natural oils by removing their polar components.
  • the application of this process to lanolin or liquid lanolin removes pesticide residues and results in products which consist, predominantly, of sterol esters.
  • the super refined products, in addition to being of extremely low pesticide residue content, are less "tacky" than the parent materials, almost colourless and essentially odourless.
  • lanolins a free lanolin alcohol content of less than 3% is an indicator of hypoallergenicity.
  • Medilan (RTM) can therefore be considered an hypoallergenic Lanolin.
  • Medilan Ultra is an odourless, white soft solid which essentially consists of lanolin sterol esters and complies with the proposed PhEur pesticide residue limits for lanolin (ppm). Both PhEur and USP compliant versions of this ultra high purity lanolin are available.
  • a yellow coloured liquid lanolin which has been molecularly distilled to comply with the proposed PhEur pesticide residue limits for lanolin (ppm) and conforms to a maximum free lanolin alcohol limit of 3%.
  • Liquid Medilan Ultra is an odourless, almost water white, oily liquid which essentially consists of liquid lanolin sterol esters and complies with the proposed PhEur pesticide residue limits for lanolin (ppm).
  • Super Hartolan contains in excess of 30% cholesterol and 20% related sterols which are responsible for its highly efficient emulsifying, moisturising and conditioning properties.
  • the synergistic action of the components enhances water-binding power well beyond that of cholesterol alone.
  • the visual analogue scale has been used to evaluate pain, itch and other sensations.
  • the scale consists of a 10cm numerically calibrated line. During the trial the volunteer is asked to rate the sensation (e.g. pain or itch sensation) by marking the line with a cross.
  • the scale can be marked with a numerical scale or left unmarked with only the ends labelled for the 2 extreme possibilities.
  • a screen was constructed to prevent the volunteer from seeing their arms during the test.
  • the volunteer was also prevented from seeing the computer screen as observation of a flare / increase in perfusion, recorded from the laser doppler scan may have affected the result.
  • Results were calculated by measuring the distance between no itch and the mark placed on the scale by the volunteer (in cm). This is a widely used method for the observation of pain and itch, but due to its subjectivity is most useful when used in conjunction with other methods such as the laser doppler analysis.
  • the DermaTempTM thermometer (available from Actamed Ltd, Wakefield, England) is a high precision hand held infrared thermographic scanner designed to detect subtle changes in skin temperature caused by underlying changes in perfusion. This therefore made it a useful complement to the scanning laser doppler measurements (see below), and it was used to record the maximum temperature on each test zone. To prevent cross contamination between test sites the probe was positioned approximately 10mm above the surface.
  • Laser Doppler fluximetry was developed a number of years ago and is used to assess blood perfusion in superficial microvascular systems of e.g. the skin.
  • Stationary laser doppler probes are contact instruments which assess blood flow over a small area, the scanning laser doppler is able to take thousands of measurements of a designated area.
  • the PeriscanTM laser doppler scanner (available from Perimed AB, Sweden) and used in this study uses a low power monochromatic beam which sequentially scans the surface of the tissue (up to 1 mm deep). At each tissue site the laser penetrates the tissue. When it comes into contact with a moving particle for example the haemoglobin in the red blood cells, a fraction of the photons become shifted according to the laser doppler principle. The speed and number of red blood cells influence the backscatter of light recorded in the scanner.
  • the backscattered light compromises a mixture of light which is shifted and non-shifted in frequency. This is detected by the scanner. As the beam moves to the next site the perfusion image is displayed on the computer screen, in addition a black and white image is shown which aids identification of the test site.
  • the scanning laser doppler is a non-contact instrument which allows readings to be taken without positioning being an issue.
  • Test materials were diluted (to 10%w/w) in either ethanol or mineral oil. However, it was noted that the mineral oil seemed to prevent the anaesthetic penetrating the skin and was therefore not used in further studies.
  • Test subjects placed their arms under a screen for the duration of the evaluation to prevent them seeing the test sites. Filter paper strips (1.5 cm 2 ) were soaked in the test solution, and applied to the forearms of test subjects. Tests were conducted in a randomised, double blind manner.
  • lauromacrogols the 9-mole ethoxylated derivative of lauryl alcohol. These lauromacrogols compounds are believed to work as anti-pruritic materials by exerting/imparting a mild anaesthetic effect to the skin. Lauromacrogol is a widely used ingredient in a number of anti-itch products.
  • Lauromacrogol 400 (Sigma product code P9641 ) was not screened in the positive control assessment it was decided to include it in the full study due to its well publicised mild anaesthetic effect.
  • the study consisted of 10 female volunteer subjects (n 10) of less than 40 years of age. All subjects met the inclusion criteria of the evaluation protocol.
  • test site was defined as the volar forearms of volunteers. Four sites per arm were used, making a total of eight test sites. Test materials were placed into vials and labelled with a letter code in order to be blind from the volunteer and the assessor. The identification letter codes are listed in Table II. TABLE Il - Identification codes (at 10% w/w)
  • PEG-9-Medilan has a weight average molecular weight of approximately 1200 Daltons and a Hydroxy! value of 40-50 mgkoH/g.
  • the evaluation was performed under ambient temperature / humidity conditions, over a single day in order to reduce temperature/humidity variations, although these parameters were not recorded.
  • test sites on the arm were then marked (delineated) using a square of filter paper as a template. Assessment was performed as detailed in the positive control assessment section.
  • test products were applied prior to histamine application. Volunteers were asked to attend three evaluation studies; during each visit 2 test products would be assessed. Test products were applied to the skin on a plaster for 1 hour. After plaster removal the test sites were left for 15 minutes to ensure any erythema caused by the plaster adhesive had subsided.
  • Histamine was then applied to the test site on a filter paper (to prevent leakage to the surrounding areas) at a concentration of 2.5mg/cm 2 for 5 minutes.
  • Hydrocortisone solution was used as a positive control as this is known to have anti-inflammatory benefits.
  • Hydrocortisone is a glucocorticoid used topically on the skin. Glucocorticoids have potent anti-inflammatory actions and suppress the immune system.
  • Hydrocortisone is a short acting glucocorticoid which prevents formation, release and activity of endogenous mediators of inflammations, including prostaglandins, kinins, histamine, lysosymal enzymes and complement (a substance consisting of nine fractions, which aids the immune response). Hydrocortisone acts by reducing the number of mast cells and thereby reducing histamine release.
  • hydrocortisone at 2% w/w and so this concentration was used in the trial. Ethanol was used as the vehicle and so served as the negative control.
  • Ethanol was used as it would remove the lipids and so aid penetration of both the histamine and PEG-9 derivatives.
  • ethanol can cool the skin and so decrease the sensitivity, however it was felt that the 15 minutes allocated for evaporation after plaster removal would prevent this from affecting the results.
  • Preliminary trials using Crodamol IPM as a penetration enhancer suggested this produced a film formation, thereby protecting the test sites and so reducing the penetration of the products.
  • Other commercially available anti-itch products use lauromacrogol as the active ingredient to reduce itch. This is normally incorporated into formulations at 3% w/w. This was included in the trial and for comparison the PEG-9 derivatives were assessed at the same concentration.
  • test products When comparing the test products to the controls (i.e. hydrocortisone and ethanol) the number of volunteers assessed was 8. When comparing to lauromacrogols this was reduced to 6, as the assessment of the products was randomised to ensure all were included in the trial.
  • controls i.e. hydrocortisone and ethanol
  • the results on the graphs in Figure 4 to 6 are for 10 volunteers for hydrocortisone and ethanol and 8 for all other products.
  • the left hand bar in each group of 3 bars relates to the reading 0 minutes after Histamine removal, the middle of the 3 bars to the reading 5 minutes after Histamine removal and the right hand bar to the reading 10 minutes after Histamine removal.
  • the results of the VAS analysis for each product are shown in Figure 4.
  • the data provided is raw data, i.e. the average score for each product. It was not possible to calculate the percentage change, as the starting (baseline) scores would be zero. Error bars are calculated from interval of confidence at a confidence level of 0.05.
  • Perfusion units The results of the perfusion units for each product are shown in Figure 5.
  • the data provided is the value for each volunteer calculated as a percentage change value from baseline (i.e. before histamine application), averaged to give a percentage increase for each product.
  • the results for the ethanol could be a result of inadequate time being allowed for evaporation of the ethanol, this may have caused a cooling effect on the skin and so reduced sensitivity to the histamine. This could also be due to the small population size, the results of a larger group of volunteers may have reduced the influence these few volunteers had on the results.
  • Figures 4 to 6 show the error bars to be large, if the study was to be performed again, a larger panel may reduce these, thus making some results more statistically significant.
  • PEG-9 Medilan appears to be the most effective at preventing a histamine provoked reaction for VAS and perfusion units. Lauromacrogol appears to be the least effective. Overall the results of this trial have shown that PEG-9 Medilan appears to be the most effective compound at preventing the itch reaction. PEG-9 Satulan performed well for the prevention of an increase in perfusion units. Lauromacrogol did not perform particularly well in the trial.
  • PEG-9 derivatives were tested as potential anti-itch materials. It was hypothesised that these compounds would demonstrate anti-itch potential through a mild anaesthetic effect on the skin. The aim of this investigation was to assess the test materials in an emulsion base and assess the differences between the liquid and insoluble portions of the samples.
  • Test solutions were made up in ethanol at 10%.
  • test panel consisted of 10 females aged 20-30. Volunteers were asked to place their arms behind a screen for the duration of the evaluation to ensure their response was based on touch response only. Ethanol solutions were applied using 1.5cm 2 filter papers which had been soaked in the test solution and applied to the skin for 1 minute. Sufficient time was allocated for the samples to fully evaporate after removal from the skin.
  • PEG-9 Medilan was assessed in ethanol to compare the mixture (including the in-soluble portion of the material) and the liquid fraction only.
  • PEG-9 Medilan is more effective at causing anaesthesia than PEG 5, 20 and 30, although this was not shown to be statistically significant. This is likely to be due to the small sample size.
  • PEG-9 Super Refined Satulan was shown to be the least effective Croda product. Looking at the trend all Croda products were shown to be more effective than Lauromacrogol at a concentration of 10%.
  • PEG-30 Medilan proved to be the second most effective candidate.
  • the liquid only sample was less effective as an anaesthetic. This suggests that the insoluble portion of the material i.e. the non-ethoxylated fraction of the Medilan, has some anaesthetic properties. However as the liquid fraction did still show significant anaesthesia (compared to ethanol), the effects of the product are not solely due to the unreacted Medilan.
  • reaction (2) is favoured.
  • RCH 2 OH produced in (7) or (8) can then undergo proton exchange (5), followed by ethoxylation (6).
  • Free PEG will also be produced by a chain transfer reaction involving two ethoxylated fatty acids:
  • the final product will be a complex mixture of ethoxylated ester (PEG-inserted), ethoxylated fatty acids, ethoxylated alcohols & free PEG
  • suitable topical delivery forms may include sprays, aerosols, liniments, lotions, bath dispersions, shampoos, drenches, ointments, pastes, creams, gels, salves and patches and may also comprise non-topical forms such as pessaries, suppositories or any other suitable dosage form such as is typically used for the delivery of cosmetically or pharmacologically active agents.
  • the formulations may accordingly comprise oil-in- water or water-in-oil or complex emulsions, or solutions or suspensions.
  • a preferred topical delivery form is a cream.
  • a suitable cream will comprise distilled water, a wax, an emulsifier and a preservative.
  • the cream may also contain an opacifier, an emollient, and/or a sunscreen.
  • the cream contains about 10% to 50% distilled water, about 5% to 25% wax, about 1% to 15% emulsifier, about 0.01- 0.25% preservative, about 1% to 10% opacifier, and about 1% to 10% emollient. All percentages are w/w based on the total weight of the composition.
  • Suitable waxes include ceresin wax, candelilla wax, camauba wax and emulsifying wax NF. Presently preferred is emulsifying wax NF in a range 5 to 25%.
  • Suitable emulsifiers include diisopropyl dimerate, octyldodecyl stearate, octyldodecyl stearoyl stearate, sorbitan sesquioleate, glyceryl stearate NSE, behenyl triglyceride, pentaerythritol tetra capra/caprylate, sucrose stearate, PEG 100 stearate, steareth-100, PPG 30 cetyl ester, PPG 50 cetyl ester, polypentaerythrital tetralaurate,
  • PEG 120 methyl glucose dioleate PEG 120 methyl glucose dioleate, C12-15 alkyl (alkyl containing 12-15 carbon atoms) benzoate, and ammoniomethylpropinate.
  • sorbitan sesquioleate in a range of 1 to 5%
  • PEG 120 methyl glucose dioleate in a range of 1 to 4%
  • Suitable preservatives include methyl paraben, propyl paraben, butyl paraben, phenoxyethyl paraben, phenoxyethyl alcohol, precipitated sulfur, and sorbic acid and other sorbates.
  • methyl paraben in a range of 0.05 to 0.15%
  • propyl paraben in a range of 0.03 to 0.1%.
  • Suitable opacifiers include behenic acid and tribehenin. Presently preferred is behenic acid in a range of 2 to 7%.
  • Suitable emollients include cetyl palmitate, diisopropyl adipate, polysorbate 20, polysorbate 80 (Tween 80), glycereth-26, sodium hyaluronate, chondroitin sulfate and allantoin.
  • polysorbate 20 in a range of 1 to 5%
  • polysorbate 80 in a range of 1 to 3%.
  • Suitable sunscreens include octyl methoxycinnamate and other cinnamates, octyl salicylate, oxygenzone, octyl dimethyl PABA and other PABA esters in ranges of approximately 5% to approximately 15%.
  • the increasing worldwide prevalence of skin cancer has led many formulators to include sunscreens in skin care products applied to exposed areas.
  • the compositions of the present invention employ ingredients providing adequate sun protection while avoiding comedogenicity and irritancy.
  • the antipruritic compositions of the present invention may also include other actives which are known to have antipruritic properties.
  • actives include menthol, camphor, phenol, lidocaine, pramoxine and hydrocortisone. This list is intended to illustrate the wide range of actives which may be incorporated and is intended to include all known antipruritic agents as well as those yet to be discovered.
  • compositions may contain camphor in a range of about 0.5% to 1.5%, menthol in a range of about 0.5% to 1.5%, and phenol in a range of about 0.5% to 1.0%.
  • the antipruritic compositions of the invention additionally comprise lidocaine and pramoxine as additional active ingredients
  • the compositions may contain about 1% to 10% lidocaine and about 1% to 2.5% pramoxine.
  • the antipruritic compositions may comprise hydrocortisone acetate as a further active ingredient.
  • the compositions Preferably contain about 1% to 5% hydrocortisone acetate.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions and may be prepared by dissolving the active ingredient in a suitable aqueous solution containing a bactericide and/or fungicidal agent and/or any other suitable preservative.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container, and then sealed and sterilized by autoclaving or maintaining at 90- 100 0 C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • Preservatives, bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric salts (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide or preservative prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol, or a softener or moisturiser such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in granule or powdered form, alone or in solution or suspension in an aqueous or non-aqueous solution in suitable machinery, with a greasy or non-greasy basis.
  • the basis may comprise one or more of a hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil such as vegetable oil, eg almond, corn, arachis, castor or olive oil; wool fat or its derivatives; or a fatty acid ester of a fatty acid together with an alcohol such as propylene glycol or macrogols.
  • the formulation may also comprise a suitable surface-active agent, such as an anionic, cationic or non-ionic surfactant such as glycol or polyoxyethylene derivatives thereof.
  • a suitable surface-active agent such as an anionic, cationic or non-ionic surfactant such as glycol or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums may be incorporated, optionally with other inorganic materials such as silicaceous silicas, and other ingredients such as lanolin or other lanolin derivatives.
  • compositions of the invention may further be used as skin moisturizers or for the provision of a film or barrier to allow both the delivery of medicaments to underlying traumatised skin (eg to wounds, burns, ulcers) or to eczematous or psoriatic skin or to areas of generalised dry or damaged skin or hair, eg following excessive exposure to the sun or wind or after radiation or chemotherapy treatments, and also to prevent the actions of airborne infections to such aforesaid traumas.
  • traumatised skin eg to wounds, burns, ulcers
  • eczematous or psoriatic skin or to areas of generalised dry or damaged skin or hair eg following excessive exposure to the sun or wind or after radiation or chemotherapy treatments, and also to prevent the actions of airborne infections to such aforesaid traumas.
  • compositions particularly for use as a sunscreen, include one or more of a moisturizer, an emollient, an emulsifier, a preservative, a dispersant, a viscosity modifier, an herbal extract, a solvent, a chelating agent, an antioxidant, a waterproofing agent, a pH adjuster, a perfume, and a protein.
  • the composition may include one or more of: titanium dioxide, zinc oxide, benzophenone-3; benzophenone-4; octyl methoxycinnamate (Parsol 1789); 3,3,5- trimethylcyclohexyl salicylate; carbomer; hydroxyethyl cellulose; lanolin alcohols; cetyl phosphate; fatty alcohols; Ci 2 to C 15 alkyl benzoate; cyclomethicone; caprylic/caphc triglycerides; mineral oil; glycerin; vitamin E; and isopropyl myristate.
  • a pharmaceutical formulation for treating itch caused by bums, by exposure to sunlight or by exposure to UV radiation comprising a composition of the invention and a physiologically acceptable carrier.
  • the carrier may therefore include excipients normally present in formulations for treating bums, such as antiseptic compounds, emollients, inorganics, humectants, moisturisers, anti-inflammatory agents, vitamins, preservatives, pH adjusters, proteins, herbal extracts, carriers/solvents, soothing/cooling agents, antioxidants, perfumes, emulsifiers and viscosity modifiers.
  • excipients normally present in formulations for treating bums such as antiseptic compounds, emollients, inorganics, humectants, moisturisers, anti-inflammatory agents, vitamins, preservatives, pH adjusters, proteins, herbal extracts, carriers/solvents, soothing/cooling agents, antioxidants, perfumes, emulsifiers and viscosity modifiers.
  • useful materials include glycerine, triethanolamine stearate, vitamin E, lanolin, zinc oxide, allantoin, calamine, sodium lactate, water, lactic acid,
  • a typical example of a formulation for an anti-itch cream is:
  • compositions of the invention also find use as carriers for one or more cosmetic or pharmaceutical active agents which are incorporated into the compositions so that they may be efficiently delivered to the skin, mucosae or other parts of the body by application of the composition thereto.
  • microemulsions include aqueous compositions suitable for An aqueous composition, suitable for topical application to the mammalian body, comprising:
  • lipid component comprising one or more lipid materials selected from lanolin, lanolin derivatives and C 12-6 o hydrocarbons, which lipid materials are present as particles emulsified by the said one or more lanolin-derived surfactant materials and having a median particle size of less than 5 ⁇ m.

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Abstract

Selon un premier aspect, la présente invention concerne de nouveaux agents antipruritiques comprenant un dérivé de lanoline PEG-9 ou PPG-9 formé par dérivatisation de lanoline ou un dérivé de lanoline possédant 9 équivalents molaires d'oxyde d'éthylène ou d'oxyde de propylène, respectivement, ou le polyéthylène glycol ou le polypropylène glycol équivalent.
PCT/GB2006/000290 2005-01-29 2006-01-30 Composes Ceased WO2006079830A1 (fr)

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GB0501857A GB0501857D0 (en) 2005-01-29 2005-01-29 Compounds
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WO2013126155A1 (fr) * 2012-02-24 2013-08-29 Bausch & Lomb Incorporated Compositions ophtalmiques comprenant des cires naturelles alcoxylées
CN113663599A (zh) * 2021-08-19 2021-11-19 浙江花园营养科技有限公司 一种制备微粒状医药级羊毛醇的方法

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EP0019720A2 (fr) * 1979-05-28 1980-12-10 BAYER ITALIA S.p.A. Préparations de mesulfen et procédé pour leur fabrication
US4567039A (en) * 1984-10-12 1986-01-28 Revlon, Inc. Hair conditioning composition and method
US5641480A (en) * 1994-12-08 1997-06-24 Lever Brothers Company, Division Of Conopco, Inc. Hair care compositions comprising heteroatom containing alkyl aldonamide compounds
DE19613424A1 (de) * 1996-04-04 1997-10-09 Goldwell Gmbh Nagellackentferner
US6224853B1 (en) * 1997-04-22 2001-05-01 Woolcombers Group Plc Aqueous compositions comprising a lipid and a lanolin-derived surfactant, and their use
DE19834812A1 (de) * 1998-08-01 2000-02-03 Beiersdorf Ag Verwendung von Sterolderivaten in kosmetischen und dermatologischen Zubereitungen zur Stärkung der Barrierefunktion der Haut
US20030125223A1 (en) * 2001-12-29 2003-07-03 Robert Denton Soy based hand cleaner and method of use
US20050008680A1 (en) * 2003-07-09 2005-01-13 The Procter & Gamble Company Composition for wet wipes that enhances the efficacy of cleansing while being gentle to the skin

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013126155A1 (fr) * 2012-02-24 2013-08-29 Bausch & Lomb Incorporated Compositions ophtalmiques comprenant des cires naturelles alcoxylées
US9375401B2 (en) 2012-02-24 2016-06-28 Bausch ÷ Lomb Incorporated Ophthalmic compositions with alkoxylated natural waxes
CN113663599A (zh) * 2021-08-19 2021-11-19 浙江花园营养科技有限公司 一种制备微粒状医药级羊毛醇的方法

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