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WO2003037395A1 - Pastille destinee a soigner des plaies - Google Patents

Pastille destinee a soigner des plaies Download PDF

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Publication number
WO2003037395A1
WO2003037395A1 PCT/IB2002/004142 IB0204142W WO03037395A1 WO 2003037395 A1 WO2003037395 A1 WO 2003037395A1 IB 0204142 W IB0204142 W IB 0204142W WO 03037395 A1 WO03037395 A1 WO 03037395A1
Authority
WO
WIPO (PCT)
Prior art keywords
wafer
wound healing
wafer according
water
surfactant
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
Application number
PCT/IB2002/004142
Other languages
English (en)
Inventor
Anthony David Auffret
Gillian Margaret Eccleston
Michael John Humphrey
Kerr Hugh Matthews
Howard Norman Ernest Stevens
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.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pfizer Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Publication of WO2003037395A1 publication Critical patent/WO2003037395A1/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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/425—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/63—Crystals

Definitions

  • the present invention relates to a wafer composition, in particular, a lyophilised wafer which comprises stable crystalline particles of a pharmaceutically active agent, particularly a wound healing agent.
  • Conventional wound dressings take the form of absorbent pads of fibrous material such as lint or non-fibrous materials such as dehydrated hydrogels.
  • the wound dressing is intended to form a barrier to external contaminants whilst allowing air to permeate the wound and allowing excess moisture to be drawn from the wound.
  • Known wound dressings may also incorporate pharmaceutically active compounds to promote wound healing.
  • pharmaceutical actives when directly applied to the surface of a wound are applied in the form of solutions, powders, sprays, ointments, creams or gels. These modes of delivery are advantageous in ensuring delivery of the medicament to the tender area of an open or closed wound.
  • one problem with such directly applied formulations is that it is difficult to provide a known amount of the active substance to the wound.
  • the active substance is not always applied evenly to the area of the wound and local concentrations, thus, vary across the wound. There is the additional disadvantage that such modes of application do not lend themselves to the controlled release of the pharmaceutically active ingredient.
  • the prior art contains a number of references to lyophilised vehicles which may enable the delivery of an active ingredient to a wound.
  • WO 97/39781 discloses a method of producing a dehydrated hydrogel comprising dispersing fibres into an aqueous solution of a hydrogel precursor material incorporating a plasticiser, the fibres incorporating cations which are capable of cross-linking said precursor material to form a hydrogel, and evaporating water to produce a dehydrated hydrogel.
  • a plasticiser is essential features of the disclosure in order to produce a stable dehydrated hydrogel.
  • the hydrogel may incorporate an active ingredient for delivery to a wound, but no details are given of the physical properties of the active material, particularly the use of crystalline particles with a surfactant to aid dispersion.
  • WO95/00184 discloses a dried hydrogel that can be cut into shape for wound healing, where freeze-drying may be employed and where further active agents can be employed. Once again, there is no mention of the use of crystalline particles with a surfactant to aid dispersion.
  • WO95/18635 discloses a pharmaceutical composition for treating a wound comprising a matrix of hyaluronic acid containing at least one peptide or protein with wound healing activity.
  • the matrix is formed by freeze-drying an aqueous solution of the peptide or protein and hyaluronic acid. Again there is no mention of the use of crystalline particles with a surfactant to aid dispersion.
  • WO99/01166 discloses a method for preparing a non-fibrous porous material being swellable but not soluble in water, said material essentially consisting of one or more polymers and one or more pharmaceutical agents, by dehydrating an aqueous solution or gel of the components and subjecting the resulting porous material to dry heat treatment.
  • the pharmaceutically active agents include protease inhibitors and metalloprotease inhibitors.
  • Dry heat treatment used in the production of the material causes cross-linking to occur so that the material does not disintegrate in water.
  • crystalline particles with a surfactant to aid dispersion and furthermore, a dry heat process is employed to stabilise the matrix.
  • US Patent no. (US) 6117437 discloses a sheet-like wound dressing containing an active substance in homogeneously dispersed form.
  • the material is prepared by coating the material onto a flat substrate and cooling or drying.
  • the examples disclose the use of organic solvents which are dried in drying channels at elevated temperature.
  • the examples do not describe the formation of wafers, only thin films, and there is no mention of the particular use of crystalline particles with a surfactant to aid dispersion.
  • German patent application no. (DE) 4328329 discloses a biomatrix formed from polysaccharides and incorporating pharmaceutically active agents for application to a wound.
  • the biomatrix may optionally include fibres. There is no mention of the use of crystalline active agents in the matrix.
  • WO00/36353 discloses freeze-dried polymer gel formulations which may comprise active agents and which may be applied to wounds. There is no specific disclosure of the physical characteristics of the active ingredients, i.e. whether crystalline materials may be employed.
  • WO02/34304 published after the priority date of the present invention, discloses self-adhesive hydratable matrices for topical therapeutic use. Once again, there is no specific disclosure of the physical characteristics of any active ingredients, i.e. whether crystalline materials may be employed.
  • those strands are vitrified, as is the case in most freeze-dried products, then they will have a brittle nature.
  • the inherent plasticity of the strand forming material will contribute to the overall flexibility of the freeze-dried material.
  • This second contribution to the flexibility is influenced by the water in the material, which will act as a plasticiser; the more water in the system, the more flexible the dried matrix will be. It is usual to state the water content as a mass fraction of the total composition e.g. %w/w or weight of water/weight of composition. If that composition contains a phase separated crystalline material, that is not a hydrated crystal, then the reported water content will underestimate the actual water content of the non-crystalline or amorphous matrix.
  • the present applicants have been involved in the development of wound healing treatments comprising crystalline pharmaceutically active wound healing agents.
  • One solution is to freeze-dry the polymer to remove water, but the efficacy of the result will depend upon the final water content and can be fraught with problems. It is possible by freeze-drying to reduce the water content of a composition to less than 2 %w/w.
  • the product In order to maintain a product at such a low water content, typically the product must be packaged with an effective barrier against water vapour ingress from the atmosphere.
  • the present applicants found that the placebo matrices had a high water content, as much as 20 %, which is thought to act as a plasticiser contributing to the flexibility of the material.
  • the placebo matrices had a high water content, as much as 20 %, which is thought to act as a plasticiser contributing to the flexibility of the material.
  • crystal growth and possibly the polymorphic transitions previously seen would be likely to occur at such high water contents.
  • higher water contents of 10-20 % prevail in the absence of an effective barrier.
  • the present invention provides a wafer composition comprising:
  • a wafer may be defined as a light and highly porous structure.
  • the wafer compositions of the present invention are stable, without requiring stabilising fibres, and provide a means for administering wound healing agents to wounds in a controlled and consistent manner.
  • the wafers are lyophilised (freeze-dried).
  • the wound healing agents comprise uPA or MMP-3 and/or -13 inhibitors.
  • Suitable wound healing agents include those particularly described in EP0568289, W09811089, WO9905096, WO9940088, US5849866, WO9005719, W09627583, WO9907675, WO9833768, WO9935124, W09929667, WO0074681 , WO9920608 and WO0005214, the compounds disclosed in which are incorporated herein by reference.
  • the wound healing agent is selected from the group consisting of 3-(4-Chloro-1-guanidino-7- isoquinolyl)benzoic acid), 2-[(4-Chloro-1-guanidino-7- isoquinolinyl)sulfonylamino]isobutyric acid), (3R)-3-( ⁇ [(1 S)-2,2-Dimethyl-1- ( ⁇ [(1S)-2-methoxy-1-phenylethyl]amino ⁇ carbonyl)-propyl]amino ⁇ carbonyl)-6- [(3-methyl-4-phenyl)phenyl]hexanoic acid) (hereinafter described as compound A), ⁇ /-Hydroxy-4-[(4- ⁇ 4-[6-(2-hydroxyethoxy)-2-pyridyl]-3- methylphenyl ⁇ -1-piperidinyl)sulfonyl]tetrahydro-2H-pyran-4-carboxamide) or a
  • the wound healing agent content in the pre-formed mixture is suitably in the range 0.1 to 300 mg/ml of mixture, more suitably 0.1 to 100 mg/ml, preferably in the range 1-100 mg/ml, most preferably 10- 60 mg/ml.
  • concentration of active ingredient to be used in the wafer depends on the activity and physical properties of the wound healing agent, the type of wound to be treated and the patient to be treated.
  • wound healing agents include other protease inhibitors, such as neutral endopeptidase inhibitors, enzyme inhibitors such as those of phosphodiesterase, nuclear hormone receptor agonists such as estrogens, growth factors and cell surface receptor modulators such as GPC receptor agonists, for example A2a agonists or antagonists and compounds active at ion channels.
  • protease inhibitors such as neutral endopeptidase inhibitors, enzyme inhibitors such as those of phosphodiesterase, nuclear hormone receptor agonists such as estrogens, growth factors and cell surface receptor modulators such as GPC receptor agonists, for example A2a agonists or antagonists and compounds active at ion channels.
  • the wafer compositions of the present invention are applied directly to open wounds and, hence, care has to be taken in applying correct efficacious doses, without achieving excessive concentrations that could lead to adverse effects.
  • This point can be illustrated with the use of selective protease inhibitors, which have been described for uPA and MMP-3 and/or - 13. These enzymes have been shown to be up-regulated in chronic ulcers, and there is evidence implicating these enzymes in the degradation of cellular matrix and the pathology of ulceration.
  • normal healing wounds require some regulated proteolysis to allow matrix remodelling and cell migration to occur. Hence it is essential that pro-healing proteases like plasmin, MMP-1 , MMP-2, MMP-9, MMP-14, and tPA are not inhibited.
  • solubility of the candidate in the formulation and wound fluid is controlled to ensure that excessive concentrations and loss of selectivity is prevented.
  • the solubility range to achieve efficacious doses without adverse effects for a range of protease inhibitors is shown in Table 1.
  • Inhibitor X in Table 1 refers to 3-(4-Chloro-1-guanidino-7-isoquinolyl)benzoic acid).
  • the wound healing agents preferably have low water solubility, suitably in the range 1 ng/ml to 10 mg/ml, preferably in the range 4 ng/ml to 5 mg/ml.
  • crystalline wound healing agent(s) may be combined with one or more other agents, which may be crystalline, amorphous or soluble in the pre-formed wafer mixture, e.g. a cytokine such as a growth hormone or a polypeptide growth factor, bacteriostatic or bacteriocidal compounds, e.g.
  • iodine, iodopovidone complexes chloramine, chlorohexidine, silver salts such as sulphadiazine, silver nitrate, silver acetate, silver lactate, silver sulphate or silver chloride, zinc or salts thereof, metronidazole, sulpha drugs and penicilins, tissue- healing enhancing agents, e.g. RGD tripeptides and the like, proteins, amino acids such as taurine, vitamins such as ascorbic acid, enzymes for cleansing of wounds, e.g.
  • pepsin for use in, for example, surgical insertion of the product in cancer tissue and/or other therapeutic agents which may be used for topical application, pain relieving agents such as lidocaine or chichocaine, emollients, retinoids, or agents having a cooling effect.
  • a wafer comprising a polymer substrate; a surfactant; and water; characterised in that the wafer further comprises stable, i.e. stable of size and form, crystalline particles of a pharmaceutically active agent.
  • Wafers incorporating such therapeutic agents may be useful for administration of active ingredient through any wound surface absorbing mucosal, or similar, surface. Suitable surfaces are present in oral, nasal, rectal and vaginal mucosae and on the surface of the eye.
  • Suitable therapeutic agents envisioned by the present invention are, thus, those which may be administered to the afore-mentioned surfaces to treat disorders related to such mucosal surfaces.
  • the mucosal surface may merely provide a suitable means of administering and absorbing a therapeutic agent for any disorder treatable in such a manner.
  • Any suitable rapidly rehydratable polymer may be used in the wafer of the present invention.
  • the polymer may be formed by a chemical reaction in situ in the aqueous solution from suitable monomers or a pre-formed water- soluble polymer may be dissolved in water to form the hydrogel.
  • Suitable polymers according to the present invention may be used alone or in combination and include: Natural Polysaccharides such as acacia (gum arabic), pullulan, inulin, agar, aiginic acid and its salts, kappa-/iota carrageenan, chitosan, gellan gum, glycyrrhizin, guar gum, hyaluronic acid/sodium hyaluronate, hyaluronic acid esters, karaya gum, locust bean gum (carob gum), pectin starch and derivatives, tragacanth gum and xanthan gum; Semisynthetic Polysaccharides such as propylene glycol alginate, CMC and CMC sodium, HEC, HEMC, HPC, HPMC and MC;
  • Synthetic Polymers such as Carbomer (different Carbopol ⁇ grades), poloxamer (Pluronic ⁇ grades), polyacrylamide glyceryl polyacrylate, PEGs, PVA and povidone; Colloidally Dispersed Solids such as microcrystalline silica, microcrystalline cellulose, microcrystalline cellulose + CMC sodium (Avicel RC-591 ) and clays (e.g. Bentonite) and proteins such as collagen and gelatin. Particularly preferred is xanthan gum.
  • a suitable concentration of polymer in pre-lyophilised mixture depends on the viscosity of the polymer.
  • a suitable aqueous concentration is in the range 0.5 to 1 %w/v of aqueous solution (5 to 10 mg/ml) with 1-30 mg/ml of active ingredient.
  • a suitable concentration is in the range of about 3 to 10 %w/v (30 to 100 mg/ml) with 1-30 mg/ml of active ingredient.
  • the purpose of the surfactant is to provide a homogenous mixture of wafer components prior to processing.
  • Suitable surfactants according to the present invention include Tween 20®, Tween 80®, Lutrol F-68® and Lutrol F-127®, most suitably Lutrol F-68 and Lutrol F-127.
  • an alkaline solution of the pre-formed wafer mixture possesses the desired properties of a surfactant and is, thus, included within the definition of surfactant according to the present invention.
  • the polymer substrate and the surfactant may comprise the same material.
  • a typical concentration for surfactant is in the range 0.02-5 %w/w based on the pre-formed (pre-lyophilised) formulation, more suitably 0.2 %.
  • the water content of the wafer according to the present invention is suitable to provide sufficient flexibility to the matrix.
  • the water content is in the region of 2-20 %w/w, suitably 2-15 %w/w, alternatively 5-20 %w/w or 13- 17 %w/w, based on the composition of the wafer.
  • a wafer according to the present invention may be prepared by forming a suspension by mixing a polymer substrate, a surfactant and a wound healing agent in water, shaping the suspension into a suitable mould and lyophilising the shaped composition.
  • the resulting wafer may be optionally sterilised using suitable techniques such as gamma irradiation or treatment with ethylene oxide.
  • Freeze-drying or lyophilisation of polymers can produce a shaped material of a highly porous nature.
  • the principle of freeze-drying is well known. An aqueous solution or mixture of a soluble polymer, a surfactant and a wound healing agent is frozen. Crystals of ice form between polymer molecules, which may be removed by sublimation on application of a vacuum. The remaining polymer forms a matrix with the residual water.
  • the freeze-drying process of the present invention comprises a two step process.
  • the initial stage which is referred to as primary freeze-drying
  • water removal occurs by the sublimation of ice.
  • secondary freeze-drying control of the final water content allows fine-tuning of the mechanical properties of the wafer.
  • the aqueous solution of polymer is cooled from room temperature to below 0 °C wherein the water molecules begin to nucleate and freeze as ice crystals. Ice crystals grow throughout the solution leading to a concentration of the residual solution. More ice forms as the temperature is lowered and consequently the residual solution becomes more concentrated. This freeze-concentrate occupies the interstitial spaces between the ice crystals and is spread throughout the volume of the original solution. If cooled sufficiently it will vitrify, forming a chemically and mechanically stable glass. The shaped biomatrix is formed in this freezing step.
  • the bulk of the water separation occurs in this step and the physical conditions are arranged such that a vacuum is applied with a calculated amount of heating to ensure that there is a heat-mass transfer.
  • a vacuum is applied with a calculated amount of heating to ensure that there is a heat-mass transfer.
  • the secondary drying step a portion of the water remaining in the unfrozen interstitial freeze-concentrate is removed.
  • the controlled application of heat, under vacuum effectively results in the removal of this portion of the residual water by desorption to the gas phase.
  • the low water content of the wafer of the present invention is an important factor in its stability and strength. It is therefore possible in the secondary freeze-drying step to reduce the water content of the biomatrix in the range of 5-20 % by weight, suitably in the region of 13-17 %. Alternatively, the water content may be reduced below these values in the drying process, down to the region of 2 %w/w, then the water allowed to equilibrate to the suitable and preferred values above by exposure to an atmosphere of an appropriate relative humidity.
  • Freeze-drying is not the only means of producing a wafer according to the present invention.
  • Electrohydrodynamic (EHD) spraying may also be used, a technique described, for example, in WO01/27365, the methods described in which are incorporated herein by reference.
  • wafers may be produced by any convenient spinning process that produces fine filaments which can be laid down in a mould or otherwise constrained into a wafer form.
  • Such technologies as might be familiar to those skilled in the art are the process of melt extrusion, which forces mixtures of components, subject to heat and pressure treatment through an orifice of defined and controllable form, and also by the process of melt spinning exemplified in US patent no. 6116880.
  • the process of sterilisation of the wafer according to the present invention by means of gamma irradiation involves exposure to gamma rays generated by a radioactive cobalt-60 source in a specially designed irradiation cell.
  • the principle underlying this sterilisation process is that high energy radiation is powerful enough to destroy completely biological contaminants without being sufficiently powerful to damage the material being sterilised.
  • a semi-solid liquid formulation, having a similar composition to that which might be used to form a freeze-dried wafer may be difficult to sterilise by conventional means.
  • Gamma-irradiation can destroy the structure (viscosity) either during the process or permanently. Loss of viscosity can lead to aggregation of insoluble particles and/or an initiation of crystal maturation with consequent perturbations of particle size distribution. This can cause significant problems in terms of the rate of release of the agent into the wound or its rate of absorption within the wound.
  • a dried dosage form can be affected by gamma-irradiation, this can result in a loss of viscosity of a rehydrated form, compared to the original solution.
  • the wafers of the present invention particularly those where xanthan gum is the polymer substrate, may be sterilised using gamma irradiation without significantly affecting the particle size distribution of the active ingredient.
  • Figure 1 shows particle size distributions for the suspension and wafers of
  • Example 4 at time zero;
  • Figure 2 shows particle size distributions for the gel suspension of Example 4 at 0, 6 and 12 weeks (40 °C);
  • Figure 3 shows particle size distributions for the gel suspension and non- irradiated wafer of Example 4 at 12 weeks (40 °C); and Figure 4 shows DSC results for the irradiated and non-iradiated wafers of Example 4 stored at 40 °C for 3 weeks (1 st and 2 nd heat from -50 to 220 °C at 5 °C/min).
  • the wound healing agent, compound A is suspended in deionised water with the aid of surfactant.
  • surfactant typically, 0.2 %w/v Lutrol F-68 is used.
  • Xanthan gum is dissolved in the drug suspension at a concentration of 0. 5 %w/v and mixed until a uniform suspension is obtained.
  • the mixture is poured in a suitable mould in a quantity commensurate with the desired size and shape of the final product.
  • the drug loading may be varied from 0.1-30.0 mg/ml of the pre-lyophilised mixture, dependent on the desired dose per unit area.
  • the cast mixture of polymer, surfactant and drug is then subjected to one of the following freeze-drying processes.
  • the mixtures, in moulds, are placed in the freeze-drier and frozen to -55 °C in stages over a period of 8 hours.
  • the stages are typically, +22 (room- temperature) to -25 °C in 3 hours; -25 to -35 °C in 2 hours; -35 to -45 °C in
  • the mixtures, in moulds, are placed in the freeze-drier and frozen to -45 °C in a single stage. Ten hours are allowed for the freezing stage. A vacuum, P ⁇ SVP (saturation vaporisation pressure), preferably 30 % of SVP, is applied and maintained for the rest of the cycle. The oven temperature is then raised to -30 °C gradually over a period of 32 hours. The primary drying stage is complete 16 hours after vacuum application. The succeeding 16 hours are considered to be part of the secondary drying stage. Subsequently, the oven temperature is increased gradually, over 12 hours, to +20 °C. The total time allotted to secondary drying is 28 hours. The total freeze-drying cycle from start to finish is 54 hours. The moulds are removed from the freeze-drier and the lyophilised wafers easily recovered.
  • P ⁇ SVP saturated vaporisation pressure
  • the mixtures, in moulds, are placed in the freeze-drier and frozen to -25 °C in a single stage.
  • a vacuum, P ⁇ SVP preferably 30 % of SVP
  • the oven temperature is then increased at 5 °C/hour to +20 °C enabling secondary drying.
  • a residual water content of 2-20 %, more preferably, 2-15 % requires a secondary drying stage of 12 hours at +20 °C.
  • the drying temperature should not exceed the collapse temperature (softening temperature) of the product.
  • the secondary drying temperature should not exceed 50 °C. More preferably, a secondary drying temperature in the range 20-40 °C, even more preferably 20-30 °C is used.
  • the moulds are removed from the freeze-drier and the lyophilised wafers easily recovered.
  • Lutrol F68 (0.12 g) was dissolved in deionised water (57.48 g ) contained in a sealable glass vial (100 ml) with manual agitation. (3f?)-3-( ⁇ [(1 S)-2,2- Dimethyl-1 -( ⁇ [(1 S)-2-methoxy-1 -phenylethyl]amino ⁇ carbonyl)- propyl]amino ⁇ carbonyl)-6-[(3-methyl-4-phenyl)phenyl]hexanoic acid) (1.80 g) was added to this solution and the mixture homogenised using a high-shear stirrer (8 mm mixer-head, 24,000 rpm for 5 minutes).
  • XG (0.60 g .Xantural 180, Kelco) was added and the vial stoppered and crimped with a metal top. This mixture was placed on a rotary mixer for at least twelve hours or until all the suspending agent was completely dissolved and a smooth, viscous suspension obtained. If necessary, the suspension may be degassed, by application of a vacuum, to remove contained air-bubbles resulting from high-shear stirring.
  • the bulk of the suspension was cast to 24-well polystyrene microplates (moulds) and freeze-drying undertaken according to Example No.3 of the present application. On completion of the freeze-drying process, wafers were removed from their moulds and divided into three equal lots, one of which was kept for reference.
  • Table 2 Mean particle sizes measured for irradiated/non-irradiated wafers and the gel suspension from which they were made.
  • Data for samples stored at 25 °C for a maximum period of six weeks produce a range of values from 43.9 to 48.8 ⁇ m with an average deviation of 0.6 ⁇ m irrespective of whether they are irradiated or not. Accelerated ageing at 40 °C produces values from 46.0 to 48.3 ⁇ m with the same deviation of 0.6 ⁇ m.
  • Reference to Figure 1 highlights the lack of variation between the particle size distributions at time zero (0 weeks) of non-irradiated wafers and wafers irradiated at 25 and 40 kGy respectively. Variations in the overall distribution are small and related to variations in sample concentration.
  • reference to Figure 2 shows significant differences in distributions for gel suspensions at 0, 6 and 12 weeks storage at the higher temperature of 40 °C. In particular an indisputable shift in peak values is clearly manifest from time zero, through six weeks to twelve weeks storage. Changes in particle size distribution between the first and last time points showing similar peak abundances of approximately 9% but a difference of 14.5 ⁇ m in the calculated mean values.
  • Figure 3 consists of superimpositions of individual measurements for a twelve-week old non-irradiated wafer and the mother suspension stored at 40 °C. Six separate measurements for both samples are made at two-minute intervals over a period of ten minutes and the differences in all values for the distributions are evident.
  • hydrogel suspensions of insoluble drug are not stable of particle size. Although it is not possible from these measurements to discern a specific mechanism for the increases in particle size, observations and analysis of less stable gel suspensions (not discussed) suggest that aggregation is certainly involved. However, it can be stated with certainty that insoluble drugs contained within freeze-dried wafers do not appear to change their size after a period of accelerated ageing or after exposure to gamma-rays.
  • the wound healing agent, compound A is suspended in deionised water with the aid of a surfactant.
  • a surfactant typically, 0.2 %w/v Lutrol F-68 is used.
  • Sodium carboxymethylcellulose (Blanose 7HF) is dissolved in the drug suspension at a concentration of 0.5-1.0 %w/v and mixed until a uniform suspension is obtained.
  • the mixture is poured in a suitable mould in a quantity commensurate with the desired size and shape of the final product.
  • the drug loading may be varied from 0.1-60.0 mg/ml of the pre-lyophilised mixture, dependent on the desired dose per unit area.
  • the cast mixture of polymer, surfactant and drug is then subjected to one of the preceding freeze-drying processes.
  • the wound healing agent, compound A is suspended in deionised water with the aid of a surfactant.
  • a surfactant typically, 0.2 %w/v Lutrol F-68 is used.
  • Low viscosity sodium alginate is dissolved in the drug suspension at a concentration of 5 %w/v and mixed until a uniform suspension is obtained.
  • the mixture is poured in a suitable mould and treated according to the previous examples.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne la composition d'une pastille comprenant un substrat polymère, un tensio-actif et de l'eau. L'invention est caractérisée en ce que la pastille comprend également des particules cristallines stables, notamment de taille et de forme stables, d'un agent permettant de soigner des plaies et pharmaceutiquement actif.
PCT/IB2002/004142 2001-11-02 2002-10-09 Pastille destinee a soigner des plaies Ceased WO2003037395A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0126389.6A GB0126389D0 (en) 2001-11-02 2001-11-02 Wafer
GB0126389.6 2001-11-02

Publications (1)

Publication Number Publication Date
WO2003037395A1 true WO2003037395A1 (fr) 2003-05-08

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PCT/IB2002/004142 Ceased WO2003037395A1 (fr) 2001-11-02 2002-10-09 Pastille destinee a soigner des plaies

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GB (1) GB0126389D0 (fr)
WO (1) WO2003037395A1 (fr)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE901838C (de) * 1948-10-02 1954-01-14 Heinz Ruether Dr Pflaster
EP0068149A2 (fr) * 1981-06-25 1983-01-05 Serapharm GmbH & Co. KG Préparation sêche contenant du fibrinogène, son obtention et utilisation
WO1990014110A1 (fr) * 1989-05-16 1990-11-29 Jean Vilain Ameliorations apportees ou se rapportant a des preparations pharmaceutiques
EP0567816A1 (fr) * 1992-04-30 1993-11-03 BEHRINGWERKE Aktiengesellschaft Utilisation d'inhibiteurs d'activateurs de plasminogène pour la traitement d'imflammations et blessures
US5660854A (en) * 1994-11-28 1997-08-26 Haynes; Duncan H Drug releasing surgical implant or dressing material
WO1999035124A1 (fr) * 1998-01-09 1999-07-15 Pfizer Limited Inhibiteurs de metalloproteases matricielles
US6093731A (en) * 1998-07-24 2000-07-25 Pfizer Isoquinolines
WO2000074681A1 (fr) * 1999-06-03 2000-12-14 Pfizer Limited Inhibiteur de metalloproteases
WO2001091553A1 (fr) * 2000-05-26 2001-12-06 Demegen, Inc. Tampon composite destine a une administration commandee de medicaments

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE901838C (de) * 1948-10-02 1954-01-14 Heinz Ruether Dr Pflaster
EP0068149A2 (fr) * 1981-06-25 1983-01-05 Serapharm GmbH & Co. KG Préparation sêche contenant du fibrinogène, son obtention et utilisation
WO1990014110A1 (fr) * 1989-05-16 1990-11-29 Jean Vilain Ameliorations apportees ou se rapportant a des preparations pharmaceutiques
EP0567816A1 (fr) * 1992-04-30 1993-11-03 BEHRINGWERKE Aktiengesellschaft Utilisation d'inhibiteurs d'activateurs de plasminogène pour la traitement d'imflammations et blessures
US5660854A (en) * 1994-11-28 1997-08-26 Haynes; Duncan H Drug releasing surgical implant or dressing material
WO1999035124A1 (fr) * 1998-01-09 1999-07-15 Pfizer Limited Inhibiteurs de metalloproteases matricielles
US6093731A (en) * 1998-07-24 2000-07-25 Pfizer Isoquinolines
WO2000074681A1 (fr) * 1999-06-03 2000-12-14 Pfizer Limited Inhibiteur de metalloproteases
WO2001091553A1 (fr) * 2000-05-26 2001-12-06 Demegen, Inc. Tampon composite destine a une administration commandee de medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BROMBERG L E ET AL: "Novel periodontal drug delivery system for treatment of periodontitis", JOURNAL OF CONTROLLED RELEASE, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 71, no. 3, 28 April 2001 (2001-04-28), pages 251 - 259, XP004234523, ISSN: 0168-3659 *

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