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WO2010133374A2 - Composition thérapeutique comprenant des microsphères - Google Patents

Composition thérapeutique comprenant des microsphères Download PDF

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Publication number
WO2010133374A2
WO2010133374A2 PCT/EP2010/003120 EP2010003120W WO2010133374A2 WO 2010133374 A2 WO2010133374 A2 WO 2010133374A2 EP 2010003120 W EP2010003120 W EP 2010003120W WO 2010133374 A2 WO2010133374 A2 WO 2010133374A2
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WIPO (PCT)
Prior art keywords
active ingredient
microspheres
composition according
polymer
microsphere
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PCT/EP2010/003120
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WO2010133374A3 (fr
Inventor
Ipsita Roy
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University of Westminster
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University of Westminster
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • This invention relates to a composition comprising microspheres for treatment of the human or animal body by therapy, in particular a composition for intraocular delivery of a product, especially a pharmaceutical product for treatment of an ocular disorder, for example macular degeneration.
  • Delivery of an active ingredient in a method of treatment of the human or animal body by therapy is important and researchers for many years have developed a wide range of techniques for improving delivery of active ingredients including employing particular crystalline forms, use of coatings, tailoring formulation of the active ingredient into a suitable composition to provide the required delivery profile. There remains a need to provide improved delivery of active ingredients, in particular in the treatment of ocular disorders.
  • Ocular disorders may occur at any age but macular degeneration is often age related and wet macular degeneration is a common cause of vision loss among the elderly.
  • macular degeneration There are two main types of macular degeneration, dry and wet.
  • the dry form occurs by the deposition of yellow spots in the macula and does not cause any loss of vision.
  • Wet macular degeneration may cause permanent central vision loss. In this condition the newly formed blood vessels under the macula tend to become thin and rupture causing bleeding and damage to the surrounding tissues.
  • a known widespread treatment for wet macular degeneration is the drug Lucentis®, available from Novartis.
  • Avastin ® available from Genentech.
  • This drug is generally administered through monthly intraocular injections, the drug is present at a high dosage initially and reduces as the drug is metabolised.
  • the method of administration for example by injection into the eye, and need for repeated surgical procedures and the cost associated with known treatments are disadvantageous. Further, disadvantageous conditions may occur due to the method of administration including conjunctival haemorrhage, inflammation of the eye, retinal tear, traumatic cataract and retinal detachment.
  • Administration of a sizeable dose of the drug means that the full dose is present in the eye at injection and decreases over time to a level where a further dose of the drug is required. The maximum appropriate dose for the patient and condition being treated will determine the minimum frequency of administration to ensure adequate levels of the drug are present until administration of the next dose.
  • EP1787643 discloses a sustained release matrix prepared from a mixture of hyaluronate and chitosan to form a gel like insoluble semisolid, which is biocompatible and erodible.
  • WO2007/019439 discloses an implant body formed in situ from a block copolymer which may be modified to have a range of solubilities.
  • WO2006/065951 discloses a long term release profile of octreotide with a biodegradable copolymer Atrigel (RTM) 1 a polylactide- coglycolide which is insoluble in an aqueous medium. The composition is fluid for delivery but solidifies in the body.
  • RTM biodegradable copolymer Atrigel
  • WO96/39095 discloses an ocular insert having a biodegradable carboxylate polymer which is bonded to a drug comprising a carboxylate functional group by means of an anhydride group susceptible to hydrolysis or a methylene diester group susceptible to in vivo degradation, and the drug is released over time by respectively hydrolysis or in vivo degradation of the bond.
  • the active ingredient must however contain certain functional groups in order to be bonded and then progressively released.
  • EP 1223917 discloses a microsphere containing a protein, a water soluble polymer, a polyanionic polysaccharide complexing agent and a cationic complexing agent selected from calcium or magnesium.
  • compositions comprising microspheres comprising a biocompatible and biodegradable water-insoluble polymer and an active ingredient which may be administered to the human or animal body to provide controlled release of the active ingredient.
  • the composition is especially suited for administration to an eye to treat an ocular disorder and which suitably exhibits a controlled release of an active ingredient over a period significantly greater than hitherto achieved, for example over more than six months, in order to treat the ocular disorder. Release of the active ingredient over a prolonged period reduces the frequency of treatment of the patient and the associated distress, inconvenience and cost of frequent surgical procedures and provides a more even concentration of the active ingredient in the eye over the treatment period.
  • the invention provides in a first aspect a composition comprising microspheres which comprise a polymer which is biodegradable, biocompatible and insoluble in aqueous solution and an active ingredient for use in a method of treatment of the human or animal body by therapy.
  • the invention particularly provides a composition
  • a composition comprising microspheres which comprise a polymer which is biodegradable, biocompatible and insoluble in aqueous solution and an active ingredient for use in treating an ocular disorder, preferably macular degeneration, for example wet macular degeneration.
  • an ocular disorder preferably macular degeneration, for example wet macular degeneration.
  • the polymer comprises a hydrophobic polymer, preferably a polyhydroxy alkanoate.
  • microspheres comprising the polymer are injectable microspheres.
  • the microspheres suitably are uniform in shape to provide for finer control over the dose of active ingredient administered.
  • the microspheres are from 0.1 to 10 microns, more preferably 0.5 to 10 microns, especially 1 to 5 microns, for example 2 microns.
  • the preferred upper limit of 10 microns is desirable as patient discomfort and blurring of vision may occur with larger microspheres.
  • the composition suitably provides "controlled release” of the active ingredient in the ocular environment.
  • the microsphere suitably biodegrades over time in the ocular environment and releases the active ingredient over at least a part of this period.
  • the size of the microsphere suitably influences the rate of release or elution of the active ingredient from the microsphere and the size of the microsphere for a particular application may be selected accordingly.
  • the microspheres disappear over time due to biodegradation so avoiding undesirable build-up of redundant microspheres in the eye.
  • controlled release refers to a release of the active ingredient from the composition over a prolonged period and where the release kinetics are slower than compared to immediate release of the active ingredient on administration of the composition.
  • the release kinetics for controlled release may involve an initial rapid release of the active ingredient up to a certain level and then the level of release tailing off or becoming constant over a further period of time.
  • a release profile of this type is known as biphasic.
  • the release profile of the active ingredient may differ depending on the environment into which the active ingredient is released.
  • Release of an active ingredient from microspheres of the invention into a phosphate buffer saline suitably provides a biphasic release profile where an initial burst release is followed by a slower release phase after several, for example at least 5 days.
  • An initial burst release phase may be due to the presence of active ingredient on the surface of the microsphere.
  • Contact lens solution may be employed in in vitro experiments to mimic the environment of the eye.
  • a biphasic profile may not be observed on release of the active ingredient into a contact lens solution and the release may be relatively constant from initial release and is suitably at a rate similar to the release observed in the second phase of a biphasic profile.
  • the active ingredient is released at a rate of 0.01 to 10 ⁇ g/mL/day, preferably 0.1 to 5 ⁇ g/mlJday and desirably at a rate of 0.5 to 3 ⁇ g/mLJday depending on the active ingredient, the loading of the active ingredient, the desired dosage rate and the environment in which the active ingredient is to be released.
  • the active ingredient is released over a period of at least one month, more preferably at least 2 months and desirably at least 4 months. Controlled release of the active ingredient is suitably maintained for at least 6 months, preferably up to 8 months, more preferably up to 12 months and desirably up to 18 months or longer for instance up to 30 months and up to 45 months.
  • the biodegradable and biocompatible polymer is suitably hydrophobic and preferably insoluble in aqueous solution so providing for comparatively slower biodegradation and slower release of the active ingredient than a hydrophilic polymer.
  • the biodegradable and biocompatible water insoluble polymer suitably comprises a polyhydroxyalkanoate (PHA).
  • PHA polyhydroxyalkanoate
  • Preferred polymers include poly(3-hydroxyalkanoates), poly(4-hydroxyalk ⁇ -ioates) and copolymers containing a PHA.
  • each alkanoate unit has from 4 to 16 carbon atoms for example poly(3-hydroxybutanoate) and poly(3-hydroxyoctanoate).
  • the polymer has a molecular weight of 10000 to 10 7 , desirably 10000 to 10 6 and especially 10 5 to 10 6 .
  • Copolymers of hydroxyalkanoates may be employed as desired, preferably a copolymer of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) poly(3-hydroxybutyrate-co-4- hydroxybutyrate) and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate).
  • the invention provides an injectable composition
  • microspheres which comprise a polyhydroxyalkanoate polymer which is biodegradable, biocompatible and insoluble in aqueous solution and an active ingredient for use in treating an ocular disorder, preferably macular degeneration, for example wet macular degeneration.
  • the polymer preferably a PHA is suitably produced by microbial fermentation.
  • polymers prepared in this way are preferred for medical applications when compared to the chemically synthesised polymers as they do not contain any metal catalysts that can trigger an undesirable cellular response.
  • Polymers of different molecular weights will provide a different degradation rate and influence the release kinetics of the active ingredient.
  • the molecular weight of the polymer in addition to the microsphere size provides flexibility for the formulator to tailor the release kinetics of the active ingredient to the desired release profile.
  • the preferred polymer is not derived from a petroleum source.
  • the microsphere may further comprise discrete parts, for example a shell and a core or an outer shell and an inner shell.
  • the discrete part may comprise the same or different materials, for example polymers.
  • the microsphere comprising the polymer may have a shell comprising a different polymer, for example a different polyhydroxyalkanoate as compared to the polyhydroxyalkanoate of the microsphere.
  • a shell is suitably employed to alter the rate of release of the active ingredient.
  • the microsphere is preferably formed by employing a water/oil emulsion wherein the polymer to be employed in the microsphere is in the oil phase and the water phase comprises a component, for example polyvinyl alcohol (PVA), to assist in the production of the emulsion.
  • PVA polyvinyl alcohol
  • the microsphere is porous.
  • the microsphere has a porosity of at least 30%, more preferably at least 35%.
  • the microsphere is not so porous as to not possess adequate structural integrity for use in treating an ocular disorder and preferably the porosity is not greater than 70%.
  • the level of porosity may affect the rate of release of the active ingredient and is suitably selected according to the desired rate of release.
  • the microsphere comprises a "double-walled" microsphere, that is a microsphere comprising a water-insoluble polymer and having a layer on part or all of the surface of the microsphere, the layer comprising a second water-insoluble polymer on the surface of the microsphere.
  • the microsphere comprises an active ingredient and a water-insoluble polymer and the layer on the microsphere covers all of the surface of the microsphere and comprises a second water- insoluble polymer, preferably a poly hydroxyalkanoate, which is different to the water- insoluble polymer in the microsphere.
  • the type of PHA in the microsphere and in the surface layer is selected from poly(3-hydroxybutyrate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) and other copolymers containing a PHA.
  • each alkanoate unit has from 4 to 16 carbon atoms for example poly(3-hydroxybutanoate) and poly(3-hydroxyoctanoate).
  • the polymer has a molecular weight of 10000 to 10 7 , desirably 10000 to 10 6 and especially 10 5 to 10 6 .
  • Copolymers of hydroxyalkanoates may be employed as desired, preferably a copolymer of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) poly(3- hydroxyoctanoate-co-3-hydroxyhexanoate) and poly(3-hydroxybutyrate-co-3- hydroxyoctanoate).
  • the microsphere comprises a polyhydroxy alkanoate selected from polyhydroxybutanoate and polyhydroxyvalerate and the surface layer comprises a different polyhydroxy alkanoate to that in the microsphere and which is selected from poly(3-hydroxybutanoate), poly(3-hydroxyoctanoate), poly hydroxyvalerate and a copolymer of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) poly(3- hydroxyoctanoate-co-3-hydroxyhexanoate) and poly(3-hydroxybutyrate-co-3- hydroxyoctanoate),.
  • the double-walled microsphere is especially useful in treating ocular disorder, preferably macular degeneration, for example wet macular degeneration.
  • the double-walled microsphere improves the release characteristics of the active ingredient and allows for fine tuning of the release profile to suit the particular active ingredient and the intended field of use.
  • the active ingredient may be selected according to the ocular disorder being treated.
  • an antibody to the growth factor may be employed.
  • an intravitreal VEGF inhibitor and more preferably LUCENTIS, available from Novartis or AVASTIN, available from Genentech, or any other commercially available active ingredient may be employed.
  • the active ingredient is suitably present at a level sufficient to provide the appropriate dosage in the patient according to the disorder being treated.
  • the cumulative release rate of the active ingredient is from 1 to 50% for an initial loading of 0.5 to 1 mg/mL, for example 0.75 mg/mL, from 0 to-20% for an initial loading from greater than 1 to 3 mg/mL, for example 1.5 mg/mL and 0 to 10% for an initial loading from greater than 3 to 10 mg/mL, for example 5mg/mL, over 36 days.
  • the active ingredient to treat wet macular degeneration suitably comprises any component known for use in the treatment of wet macular degeneration and preferably comprises a protein, for example an antibody.
  • the active ingredient is suitably stable in the microsphere.
  • controlled release of the active ingredient is not compromised by degradation or lack of stability of the active ingredient.
  • composition may suitably be administered as microspheres or as a solution comprising the microspheres.
  • the invention provides an aqueous product comprising microspheres in an aqueous solution, the microspheres comprising a biodegradable and biocompatible water-insoluble polymer and an active ingredient for use in treating an ocular disorder particularly macular degeneration, for example wet macular degeneration.
  • composition and aqueous solution according to the invention may be employed by injection into an organ of a patient or into an eye for treatment of an ocular disorder.
  • the composition or solution is injected in a manner known to those skilled in the art but the controlled release of the active ingredient results in less frequent injections as compared to conventional treatments, for example six monthly as compared to monthly injections.
  • the microspheres may be produced using a known process as desired although fine control over the particle size distribution may be difficult to achieve.
  • microspheres having a uniform particle size preferably with a mean particle size of 0.1 to 10 microns, more preferably 0.5 to 8 microns especially 0.5 to 5 microns, for example 1 micron and 2 microns, may be produced by optimising the time of incubation, the rate of stirring and the concentration of the materials employed in the production process. Desirably, at least 90% of the particles have a particle size not more than 5 microns.
  • the invention provides a process for producing a biodegradable and biocompatible polyhydroxyalkanoate polymer using a microbial fermentation process
  • the process for producing a biodegradable and biocompatible polyhydroxyalkanoate polymer using a microbial fermentation process comprises growing a seed culture of Bacillus cereus SPV in nutrient broth, overnight at 3O 0 C and using this to inoculate a production medium.
  • fermentation is carried out in fermenters sterilised with Kannan and Rehacek medium and sterilised glucose and soybean dialysate is added to the fermenters aseptically before inoculation, for example, in a 20 litre fermenter, with 1.4 L of a 24 h inoculum culture.
  • the pH is suitably adjusted to 6.8 using alkali, for example sodium hydroxide and dissolved oxygen tension may be optimised and for example is initially set at 100% air saturation.
  • the oxygen tension is not controlled during the fermentation, agitation is employed, for example at an impellor speed of 250 rpm, the air flow rate at 1vvm and a temperature at 3O 0 C.
  • a preferred process is described in the article by Vallappil et al. Journal of Biotechnology 132 (2007) 251-258.
  • the invention also provides a process for producing a biodegradable and biocompatible polyhydroxyalkanoate polymer microspheres, comprising mixing an active ingredient with a reagent to produce an active/reagent solution, mixing the active/reagent solution with a solution of a biodegradable, biocompatible water insoluble polymer to produce an active ingredient/polymer suspension, combining the suspension with an aqueous solution of a reagent, agitating and removal of the solvent to produce a polyhydroxyalkanoate microspheres containing the active ingredient.
  • the process comprises mixing an active ingredient preferably a solution of the active ingredient with a reagent, preferably polyvinyl alcohol solution.
  • a reagent preferably polyvinyl alcohol solution.
  • a solution of the polymer in an organic solvent, for example chloroform is added to the reagent and the active ingredient, desirably with stirring, for example ⁇ t 600rpm to produce a mixture comprising an active ingredient and the polymer.
  • the mixture is suitably a solution.
  • this mixture is added to a reagent, for example a polyvinyl alcohol solution and agitated.
  • the solvent is suitably evaporated to leave polymer microspheres with encapsulated active ingredient.
  • the microspheres may be washed, for example with water and dried.
  • the microsphere is preferably produced from a solid-oil-in-water emulsion.
  • a solid-oil-in-water emulsion solvent extraction/evaporation technique is employed to produce these microspheres according to the invention.
  • microspheres having a uniform particle size enable good quality control over the level of active ingredient contained in the microsphere to be maintained to the benefit of the medical practitioner prescribing a particular dose and economically in reducing the risk of higher than intended levels (and so cost) of the active ingredient being present in the microsphere.
  • Example 1 Production of poly (3-hydroxybutyrate), PQHB), microspheres with entrapped Bovine Serum Albumin (BSA)
  • a solid-oil-in-water encapsulation method was employed to entrap different concentrations (0.75 mg/mL, 1.5 mg/mL and 5 mg/mL) of protein (bovine serum albumin (BSA)) within the poly(3-hydroxybutanoate), P(3HB) microspheres.
  • BSA bovine serum albumin
  • PVA polyvinyl alcohol
  • This protein-polymer suspension was then added to a final emulsion of 0.1% PVA in chloroform and stirred at 800 rpm for 4 hours. After solvent evaporation the microspheres formed were washed with water and dried.
  • the particle size distribution curves of the microspheres were obtained using a Malvern Mastersizer Particle size analyser. 50% of the measured particles had a mean particle size from 1.5 to 2.0 microns and 90% were below 5 micron in size range. The results of this analysis are shown in Figure 2. The measured sizes were compared with the SEM photomicrograph of Figure 1 to verify accuracy.
  • microspheres with an average size of 2 microns were obtained.
  • For ophthalmic delivery particle size plays a crucial role. An increase in size above 10 microns can cause patient discomfort and blurring of vision.
  • the 2 micron sized microspheres are suitable for use in intraocular drug delivery.
  • the level of BSA contained in the microspheres was measured by dissolving the microspheres in chloroform and then extracting the BSA into an aqueous phase. The amount of BSA was then quantified using the Bradford assay (Bradford, M. 1976 Analytical Biochemistry VoI 72, pp248-252.) The level of BSA in the microsphere or encapsulation efficiency was then calculated.
  • the % of surface associated protein on the microspheres with different BSA loadings were determined by immersing a known amount of the microspheres in phosphate buffer saline (PBS) for 15 minutes and quantifying the BSA released using the Bradford assay.
  • PBS phosphate buffer saline
  • the total amount of BSA that diffused into the aqueous PVA solution during encapsulation of BSA in the microsphere preparation was also quantified. The results obtained are shown in Figure 3. The highest encapsulation efficiency value achieved was around 70%. The amount of microsphere surface associated protein was relatively low and the amount of protein lost in the PVA solution was the lowest in the 0.5% BSA loading, i.e. the condition with maximum encapsulation efficiency.
  • the protein encapsulation was also qualitatively determined by staining the BSA loaded microspheres with Coomassie Blue (Sample b) and comparing with unloaded PHA microspheres (Sample a) as shown in Figure 4. The colour observed for the BSA encapsulated microspheres (Sample b)) was distinctly stronger, indicating successful entrapment of the BSA into the microspheres.
  • microspheres produced according to Example 1 were immersed in phosphate buffer saline (PBS) and contact lens solution (Bausch and Lomb Multi Purpose Solution for soft contact lenses) at 37 0 C for 1 , 3, 7, 14 and 30 days. These were then observed using Scanning Electron Microscopy (SEM) and the results are shown in Figure 5 (phosphate buffer saline) and Figure 6 (contact lens solution) with the time period of immersion and the magnification shown in the caption for each image.
  • PBS phosphate buffer saline
  • contact lens solution Bousch and Lomb Multi Purpose Solution for soft contact lenses
  • the results show a relatively higher burst release of BSA, after 24 hours, in PBS solution as compared to that in contact lens solution. However, the total amount released is very small even in PBS 1 i.e., a maximum value of 1.8%.
  • the results for the contact lens solution indicate that, advantageously, there will be no or minimal burst release of the drug when the drug loaded microspheres are used for intraocular drug delivery.
  • the long term release of the entrapped BSA was measured. The results are shown in Figures 8 and 9.
  • the release kinetics into PBS exhibited a biphasic release profile where an initial burst release was followed by a slower release phase. This biphasic profile was not observed in the release into contact lens solution.
  • the initial release phase may be attributed to the surface associated protein as the higher burst release was observed with the microspheres which had a higher percentage of surface bound protein.
  • the amount of BSA released varied according to the level of BSA in the microspheres.
  • the level of active ingredient may accordingly be tailored according to the desired level of active ingredient to be released.
  • the time required for 100% release is 10 months in contact lens solution and a few days in PBS whereas in the 0.075% BSA loading the time required is less than five months.
  • the BSA trapped in the microspheres was released slowly and the results illustrate that microspheres according to the invention have the potential to be used for long term intraocular drug delivery.
  • Example 4 Stability of BSA entrapped in the microspheres and released in to PBS The structural integrity of the entrapped BSA which is then released, was studied using Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis.
  • Lane 1 provides a molecular weight (M w ) marker
  • Lanes 2, 5, and 8 show normal BSA solution used as controls
  • Lanes 3 and 4 show BSA released from microspheres into PBS and contact lens solution respectively on day 1
  • Lanes 6 and 7 show BSA released from microspheres into PBS and contact lens solution respectively on day 14 and Lane 9, BSA released from microspheres into PBS on day 28 of the in vitro release study.
  • compositions produced according to Examples 1 to 4 wherein the BSA component is replaced with AVASTIN or LUCENTIS provide products which have desirable release kinetics, stability, diffusion characteristics of the active ingredient and provide excellent controlled release of the active ingredient in treating ocular disorders, for example wet macular degeneration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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Abstract

La présente invention concerne une microsphère injectable comprenant un principe actif pour le traitement d'un trouble oculaire, par exemple la dégénérescence maculaire de forme humide, et qui offre une libération contrôlée du principe actif sur une période de temps prolongée, ce qui permet une réduction de la fréquence d'injection par rapport aux traitements connus.
PCT/EP2010/003120 2009-05-20 2010-05-20 Composition thérapeutique comprenant des microsphères Ceased WO2010133374A2 (fr)

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Application Number Priority Date Filing Date Title
GB0908685A GB2470378A (en) 2009-05-20 2009-05-20 A controlled release composition for intraocular delivery of a therapeutic agent
GB0908685.1 2009-05-20

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WO2010133374A2 true WO2010133374A2 (fr) 2010-11-25
WO2010133374A3 WO2010133374A3 (fr) 2011-01-13

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2022208027A1 (fr) * 2021-03-31 2022-10-06 Chanel Parfums Beaute Composition cosmétique comprenant au moins un polyhydroxyalcanoate

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