WO2001010414A1 - Microspheres presentant une liberation lente - Google Patents

Microspheres presentant une liberation lente

Info

Publication number
WO2001010414A1
WO2001010414A1 PCT/US2000/021038 US0021038W WO0110414A1 WO 2001010414 A1 WO2001010414 A1 WO 2001010414A1 US 0021038 W US0021038 W US 0021038W WO 0110414 A1 WO0110414 A1 WO 0110414A1
Authority
WO
WIPO (PCT)
Prior art keywords
microspheres
active agent
leuprolide
drug
polymer
Prior art date
Application number
PCT/US2000/021038
Other languages
English (en)
Inventor
Bagavathikanun Chithambara Thanoo
James Murtagh
Original Assignee
Oakwood Laboratories L.L.C.
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 Oakwood Laboratories L.L.C. filed Critical Oakwood Laboratories L.L.C.
Priority to AU65104/00A priority Critical patent/AU6510400A/en
Publication of WO2001010414A1 publication Critical patent/WO2001010414A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides

Definitions

  • This invention relates to microspheres containing a polypeptide More particularly, this invention relates to biodegradable microspheres containing LH-RH or its analogs for administration which provide continuous slow release of LH-RH or its analogs into a physiological medium
  • Microcapsules and Microspheres formed from various natural and synthetic polymers and resins have become popular delivery vehicles for various active agents such as drugs, diagnostic reagents and the like
  • Degradable microcapsules and microspheres are of particular interest for use in so called “depot” formulations, where delivery of the active agent over an extended period of time is desired.
  • Sustained release formulations have two generally recognized drug release profiles
  • the first release profile is characterized by an initial burst of released drug followed by a continuous supply of an effective amount of the drug over an extended period of time
  • the initial burst is controlled by diffusion of drug located on the external surfaces of a microsphere or microcapsule into a physiological medium upon administration After the initial diffusion phase, the drug release is continuously released and the rate of release is essentially controlled by degradation of the polymeric binder or matrix material from which the drug containing microsphere or microcapsule is made
  • the second type of release profile is characterized by not having an initial burst at all Without an initial burst, the release of drug is essentially controlled by degradation of the polymer binder or matrix
  • leuprolide acetate is a drug wherein an initial burst upon administration may be desirable
  • Leuprolide acetate is an agonist derivative of Lipnizing Hormone
  • leuprolide acetate acts by suppressing testosterone levels
  • the presence of testosterone is well known to promote the growth of cancerous cells in the prostate
  • leuprolide acetate offers an alternative to an orchiectomy (surgical removal of the testicles), or estrogen administration
  • the mechanism for testosterone release is generally known and it has been determined that upon administration of leuprolide acetate there is an initial increase in testosterone levels
  • the versatile process as disclosed by Applicants allows the user to prepare microspheres containing leuprolide acetate with either an intial burst or no initial burst release profile It is believed that leuprolide acetate microspheres having an initial burst may combat the increase of testosterone observed upon initial administration and as such, is important for the palliative treatment of prostate cancer Alternatively, therapeutic sustained release applications having no initial burst release can be made using the same process This is advantageous for those active agents that do not need an initial burst for their therapeutic treatment. Thus, it is desirable to be able to produce microspheres having any desired amount
  • a difficulty with obtaining a constant rate of drug release after the initial burst is the size of the drug particles or drug areas within the microsphere
  • the sizes of the drug particle or area within a microsphere/microcapsule will affect the release of the drug into the surrounding medium Where large areas or large particles of drug are observed, a concentration gradient exists and it is expected that the drug release will be higher in those areas as the polymer binder degrades This can result in secondary or subsequent bursts that are undesirable and difficult to control
  • the drug particles are very small or finely integrated within the surrounding polymer matrix, the release of drug into the surrounding medium will be much more uniform and regular
  • Another problem with controlling drug release is the degree of porosity of the microsphere Large pore areas can affect diffusion of the drug into the surrounding medium If the degree of po
  • pores having large areas filled with drug are not desirable for a well controlled and regulated continuous drug release.
  • the present invention is generally directed to continuous release microspheres for releasing effective amounts of a drug into a surrounding physiological medium
  • the microspheres comprise a polymer of glycolic acid or lactic acid or a copolymer of glycolic and lactic acids
  • An active agent is homogeneously distributed within a matrix of the polymer or copolymer wherein an average number and size of the active agent in a particular unit area is substantially the same as a second average number and size of the active agent in a different unit area of the microsphere
  • the active agent is hereinafter defined as a drug or substance used as a medication or in the preparation of medication
  • active agents include steroids, diuretics, carbohydrates, amino acids, proteins, enzymes, peptide hormones, analgesic agents, histamine and antihistaminic agents, cardiovascular agents, local anaesthetic agents, antimalarials, antibiotics, antineoplastics, CNS depressants and stimulants, adrenergic agents, cholinergics, sulfonamides
  • the microspheres have an average cross-sectional porosity less than 10% and still, more preferably, less than 5% of the total cross-sectional area
  • the inventive microspheres release drug in a highly uniform and well controlled rate
  • the copolymer preferably has an average molecular weight from about 26,000 to about 36,000 and a ratio of glycolide to lactide of about 1 1
  • the invention is directed to microspheres wherein the active agent is leuprolide
  • the leuprolide containing microspheres have an average particle size of from about 10 ⁇ m to about 40 ⁇ m, and an active agent loading of at least about 9%. More preferably, the leuprolide containing microspheres have an active agent load of at least about 15% It has been found that active agent 15% or greater is effective for providing a leuprolide containing microsphere with a desired initial burst drug release profile
  • the slow continuous release microspheres release drug from the microsphere by essentially polymer degradation in the aqueous physiological medium
  • the drug within the microsphere is continuously released in an effective amount from each said microsphere over a period of about 30 days
  • the active agent can be effectively released for longer periods of at least 90 days or again, depending on the polymer composition and choice of active agent for a period of at least 120 days
  • the present invention is directed to advantageously substantially non porous agent containing polymer bodies, and more particularly to microspheres with excellent homogeneity of drug distribution throughout.
  • the microspheres produced according to the invention are ideal for carrying drugs, diagnostic reagents, or various other active agents.
  • the microspheres of the present invention can be advantageously produced by a simple, continuous, economic and efficient process which produces a product having uniform characteristics throughout the production cycle.
  • pore is hereinafter defined as interstices or areas within the polymer matrix that do not contain polymer or any other inclusion other than the drug or active agent.
  • the pore can be a void or space or alternatively, a void that has been filled or partially filled with, for instance, a drug retaining substance.
  • Drug retaining substances are those substances as disclosed in, for example, U.S. Patent No. 5,631,021 to Okada et al.
  • the active agent can be any agent for which encapsulation or interspersion within a small polymer body is desired.
  • the active agent is a drug or substance as defined above and the microspheres are intended for the delivery of such drug or substance to a patient in need thereof.
  • suitable drugs and other active agents may be found in U.S. Patent Nos. 5,407,609, 4,767,628, 3,773,919 and 3,755,558, all incorporated herein by reference.
  • LH-RH agonists such as leuprolide, triptorelin, goserelin, nafarelin, historelin and buserelin
  • LH-RH antagonists LH-RH antagonists
  • somatostatin analogs such as octreotide, human, salmon and eel calcitonin, growth hormones, growth hormone releasing hormones, growth hormone releasing peptide, parathyroid hormones and related peptides, interferon, erythropoietin, GM-CSF, G-CSF, thymosin, antitrypsin, enterostatin, and chemotherapy drugs, antibiotics and analgesics for regional administration.
  • An especially preferred drug for use in the instant invention is leuprolide.
  • solvents for the active agent will of course vary depending upon the nature of the agent. Typical solvents that may be used in the dispersed phase to dissolve the active agent include water, methanol, ethanol, dimethyl sulfoxide (DMSO), dimethyl formamide, dimethyl acetamide, dioxane, tetrahydrofuran (THF), methylene chloride, ethylene chloride, carbon tetrachloride, chloroform, lower alkyl ethers such diethyl ether and methyl ethyl ether, hexane, cyclohexane, benzene, acetone, ethyl acetate, and the like. Selection of suitable solvents for a given system will be within the skill in the art in view of the instant disclosure.
  • Polymers useful in the present invention can also vary. Examples of polymers known to those of ordinary skill in the art, and useful in the present invention, may be found in, for example, U.S. Patent Nos. 4,818,542, 4,767,628, 3,773,919, 3,755,558 and 5,407,609, incorporated herein by reference. In selecting a particularly desirable polymer for a given system, numerous factors can be considered for purposes of producing a product having the desired clinical characteristics such as biodegradability (e.g., release profile) and biocompatibility. Once one of ordinary skill in the art has selected a group of polymers that will provide the desired clinical characteristics, then the polymers can be evaluated for desirable characteristics that will optimize the manufacturing process.
  • biodegradability e.g., release profile
  • a polymer that will interact with the active agent in a manner that will facilitate the processing of the microspheres, enhance drug load, enhance solvent removal from the dispersed phase or inhibit drug migration from the dispersed phase into the continuous phase.
  • One consideration in selecting a preferred polymer is the hydrophilicity/ hydrophobicity of the polymer. Both polymers and active agents may be hydrophobic or hydrophilic. Where possible it is desirable to select a hydrophilic polymer for use with a hydrophilic active agent, and a hydrophobic polymer for use with a hydrophobic active agent.
  • a hydrophilic polymer can be expected to yield low residual solvent with a hydrophilic drug, such as a hydrophilic peptide
  • a hydrophilic drug such as a hydrophilic peptide
  • the drug has a tendency to help eliminate hydrophobic solvent from the dispersed phase droplets quickly and efficiently
  • a greater drug load tends to correlate to lower residual solvent concentrations
  • this effect may not uniformly apply to non-peptide drugs Nevertheless, it should follow that active agents that enhance the elimination of solvent from the dispersed phase droplet, without concomitant drug loss, yield superior products
  • molecular weight of the polymer While the molecular weight of the polymers will obviously impact on the product characteristics such as release rate, release profile and the like, it can also impact the process of producing the microspheres Higher molecular weight polymers are typically associated with a more viscous dispersed phase, resulting in larger particles or increased difficulties in obtaining small particles and, in some instances, increased residual solvent By contrast, lower molecular weight polymers are typically associated with slower solidification because the polymer tends to be more soluble In the preferred system, higher drug loading and enhanced incorporation efficiency has been found to result from the use of higher molecular weight polymers
  • One advantage of the inventive process is its ability to form well formed, essentially spherical, low residual solvent microspheres with high molecular weight polymers and, hence, viscous dispersed phases
  • the particular selection will also depend upon the desired product characteristics For example, the higher the molecular weight, the longer the degradation time in the body and the longer the duration of drug release Still further, the particular polymer concentration employed can effect the system, not
  • a viscous dispersed phase leads to less drug diffusion into the continuous phase during solidification. In some systems this may also result in higher residual solvent.
  • polymer concentration in the dispersed phase will be from about 5 to about 40%, and still more preferably from about 8 to about 30%.
  • Especially preferred polymers are homopolymers of lactic acid, or copolymers of lactic acid and glycolic acid, i.e., poly(lactide-co-glycolide) or "PLGA" polymers.
  • the ratio of lactic acid residues to glycolic acid residues can vary, and will typically range from 25:75 to 75:25, although even a 10% glycolide could find use since high lactide content results in lower viscosity and higher solubility.
  • Preferred copolymers for 30 day formulations comprise at least about 50% lactic acid residues, such as 50:50 or 75:25 polymers.
  • Preferred copolymers for 90 or 120 day formulations comprise a higher amount of the lactide monomer to glycolide monomer.
  • the 90 or 120 day formulations comprise a homopolymer of polylactide.
  • Poly(lactide-co- glycolide) copolymers and polylactide homopolymers are commercially available from a number of sources and can be readily prepared by conventional synthetic routes. Boehringer Inglehiem produces suitable polymers under the designations RG 502, RG 502H, RG 503, RG 503H, RG 752, RG 756, R202H and others. With the preferred LH-RH microspheres RG502H and RG503H are used in the dispersed phase in concentrations of 23% and 14% respectively.
  • Such copolymers also may be made by polymerizing lactic acid and glycolic acid or, preferably, by polymerizing the cyclic dimers of lactic acid and glycolic acid, namely lactide and glycolide, as described in, for example, U.S. patent number 3,773,919, incorporated by reference above. Selection of a suitable polymer for a given system would be apparent to those of ordinary skill in the art in view of this disclosure.
  • Solvents for the polymer will also vary depending upon a number of factors, including the nature of the polymer, the active agent, toxicity, compatibility with other solvents in the system and even the use to which the microsphere will be put. Thus, in addition to dissolving the polymer, the solvent must be immiscible with the continuous phase in order to form droplets, highly volatile for optimum evaporation efficiency, and desirably non-flammable for safety reasons.
  • Solvents suitable for the preferred poly(lactic) or poly(lactide-co-glycolide) polymers include methylene chloride, chloroform, ethyl acetate, substituted pyrrolidone and the like. In some instances, the solvent for the active agent will be the same as the solvent for the polymer.
  • Some drugs typically diagnostic agents such as radioactive inorganic salts used in imaging analysis, are not soluble or only slightly soluble in organic solvents. In these instances, a fine, sub-sub micron size powder can be directly suspended in the polymer solution to form microspheres. Although resort to this will be rare in drug delivery, it may prove useful with diagnostic agents. Selection of other solvents useful in accordance with the process of the invention will be within the skill in the art in view of the instant disclosure.
  • the dispersed phase is a true, homogeneous solution which may be prepared by mixing the polymer, solvent and active agent together to form a solution.
  • separate solutions of polymer and active agent can be prepared, each in its own solvent, and subsequently mixed to form the dispersed phase solution.
  • the dispersed phase must be formed as an emulsion. For example, when a given proteinaceous drug is dissolved in a suitable active agent solvent, the resulting solution may be completely immiscible with a solution of the polymer in a particular polymer solvent.
  • the drug and drug solvent may be emulsified with the polymer and polymer solvent to form a dispersed phase emulsion.
  • a w/o/w emulsion is formed.
  • the dispersed phase can be prepared by forming a direct suspension of the active agent in a polymer solution.
  • the dispersed phase heretofore described is dispersed or emulsified in a continuous phase in order to form droplets or inclusions of dispersed phase in the continuous phase.
  • the terms emulsified or dispersed are intended in their broadest sense as meaning discrete regions of dispersed phase interspersed within the continuous phase.
  • the noted inclusions will typically occur as generally spherical droplets, but may in some instances be irregular inclusions due to particular emulsification conditions.
  • Any suitable medium in which the dispersed phase will form droplets or inclusions may be used as a continuous phase, with those that provide a maximum solvent sink for the dispersed phase solvent being especially desirable.
  • the continuous phase will also contain surfactant, stabilizers, salts or other additives that modify or effect the emulsification process.
  • Typical surfactants include sodium dodecyl sulphate, dioctyl sodium sulfo succinate, span, polysorbate 80, tween 80, pluronics and the like.
  • Particular stabilizers include talc, PVA and colloidal magnesium hydroxide.
  • Viscosity boosters include polyacrylamide, carboxymethyl cellulose, hydroxymethyl cellulose, methyl cellulose and the like. Buffer salts can be used as drug stabilizers and even common salt can be used to help prevent migration of the active agent into the continuous phase.
  • PVA and other stabilizers may have a tendency to precipitate as solids from the continuous phase. In such instances a paniculate stabilizer might be used.
  • Suitable salts such as sodium chloride, sodium sulfate and the like, and other additives would be apparent to those of ordinary skill in the art in view of the instant disclosure.
  • the continuous phase is water.
  • the aqueous continuous phase will typically include a stabilizer.
  • PVA is present in an amount of about 0.35%.
  • Other stabilizers suitable for use in the continuous phase would be apparent to those of ordinary skill in the art in view of the instant disclosure.
  • a viscous continuous phase and a higher concentration of stabilizer may be necessary to obtain the desired microspheres.
  • the dispersed phase can be made more viscous by cooling, increasing the molecular weight of the polymer or increasing the concentration of the polymer.
  • adjusting the viscosity of the continuous phase further complicates the process, and use of a dispersed phase with a high viscosity makes it more difficult to obtain small particles.
  • cooling the dispersed phase will have a tendency to reduce the solubility of the dispersed phase solvent therein, which can lead to higher residual solvent contents and/or longer solvent removal periods.
  • Drug crystallization might also be a problem with cooling.
  • An advantage of the preferred embodiment of the invention is that, because foaming is not a significant impediment, it is not necessary to cool or otherwise adjust the viscosity of the phases in order to obtain small particle sizes.
  • the present process enables one to obtain small particle sizes even when it is necessary to use a viscous dispersed phase, without having to adjust the viscosity of the continuous phase to prevent foaming. This simplifies the process and reduces costs.
  • scaling up to larger batches, including production level batches becomes a simple matter of running the process longer.
  • the outlet tube was connected to a 7 liter jacketed bio-reactor from Applikon.
  • One of the top plate ports of the Applikon was connected to the vacuum pump, another to a dry 0.2 ⁇ m filter to serve as the air inlet, another served as the inlet from the Silverson, and the fourth served as the harvest line.
  • Example 1 This is an example of a typical procedure used to prepare microspheres of poly(lactide-co-glycolide) and Leuprolide (LH-RH agonist derivative).
  • the hydrophilic polymer RG503H is a 50:50 copolymer of poly(lactide-co- glycolide) from Boehringer Ingelheim having an inherent viscosity of 0.42 dL/g. This polymer has a weight average molecular weight (M w ) on the order of 30,000.
  • a solution of this polymer was prepared by dissolving 7.0 grams RG503H in 36 g dichloromethane.
  • the drug solution was prepared separately by dissolving 1.00 g Leuprolide acetate in 8.56 g methanol.
  • the dispersed phase (DP) was prepared by combining the Leuprolide solution and the polymer solution with mixing. The DP thus formed is a homogeneous light yellow, relatively clear solution.
  • the DP was then transferred into a 124 mL pressure addition funnel and connected to the DP inlet to of the Silverson unit through a micrometer Teflon needle valve. Head pressure was applied to the addition funnel (10 psi) above the continuous phase (CP). The stopcock of the addition funnel was kept closed until the DP addition started.
  • the continuous phase (CP) was 0.35% polyvinyl alcohol (PVA) solution (w/v) prepared in a 7 liter beaker by dissolving 14.0 g PVA (cold water soluble, MW
  • the CP addition tube to the Silverson unit from the CP tank used a peristaltic pump for flow control.
  • the outlet tube of the Silverson unit was connected to the solvent evaporation tank, which is a 7 liter Applikon reactor with a jacketed vessel and lip-seal stirrer assembly.
  • the Silverson unit was primed with CP and trapped air in the cell was removed by opening the bleed valve.
  • the stirrer motor of the Silverson was turned on to 7000 rpm and the CP and the DP were introduced into the reactor simultaneously.
  • the required flow rate of CP and DP were achieved and maintained constant using the peristaltic pump (for CP) and needle valve (for DP).
  • the addition time was 2 minutes, during which 52.6 grams of DP and 4000 mL of CP were introduced to the mixer at a constant rate of flow.
  • the microspheres were formed in the Silverson unit and delivered as a suspension into the solvent evaporation tank.
  • the head space air was constantly replaced using the vacuum pump.
  • the air flow through the head space was approximately 29 standard liters per minute.
  • the temperature of the evaporation tank was increased from 25° to 42 °C and maintained for 3 hours. The higher temperature and air sweep helped the system to achieve lower residual solvent in the microspheres.
  • the system temperature was lowered to 25 °C and the microspheres harvested by pressure filtration (5-20 psi) onto a 5 ⁇ m filter using a 2000 mL stirred cell assembly (M-2000 from Amicon).
  • the microspheres were washed with 2000 mL WFI and freeze dried in bulk as a concentrated suspension in
  • microspheres prepared according to this example had 9.88% drug load showing 79% drug incorporation efficiency.
  • Microscope analysis showed that the microspheres were spherical and the particles ranged from non-porous to partially porous. Small particles were non-porous while larger particles showed some porosity.
  • the bulk density of the microspheres was 0.588 g/cc.
  • the particle size distribution analysis showed that 50% of the particles were below 18 ⁇ m (volume distribution), and 80% of the particles were between 7 and 36 ⁇ m.
  • the residual solvent methylene chloride or methanol
  • Example 2 As illustrated by this example, a significant advantage of the preferred continuous flow process according to the invention is the product consistency during processing. Prior processes are unable to produce microspheres having virtually identical characteristics at the end of the production run as the ones produced at the beginning and middle of the run This is a significant commercial advantage
  • the microspheres were prepared in the same manner as in Example 1 , using 25% excess DP and CP
  • the DP contained 8 75 g RG503H, 1 25 g Leuprolide acetate, 45 g methylene chloride and 10 7 g methanol
  • the CP was 5000 mL 0 35% PVA
  • the microsphere suspension produced in the Silverson reactor was not transferred to the solvent removal tank Instead, each 1000 mL fraction (the collection time for each fraction being approx. 24 seconds) were collected in a 2000 mL beaker Thus, five fractions of equal volume was collected
  • the microspheres from each fraction were separated by filtration, freeze dried in bulk and compared.
  • Example 3 In this example, a hydrophobic polymer was used Boehringer Ingelheim RG502 is a 50 50 co-polymer of PLGA with an inherent viscosity of 0 2 dl/g
  • the preparation procedure was similar to Example 1, except for the composition of the DP
  • a polymer solution was prepared by dissolving 8 77 g RG502 in 20 g dichloromethane
  • the drug solution was separately prepared by dissolving 1.25 g leuprolide in 4 g methanol
  • the polymer and drug solutions were mixed to form the DP.
  • the drug incorporation efficiency of the resulting microspheres was 65% and the microspheres had a drug load of 8 17%
  • Microscope analysis showed that the microspheres had spherical geometry and were porous
  • the bulk density of the microspheres was 0 23
  • the particle size distribution analysis showed that 50% of the particles were below 25 6 ⁇ m (volume distribution), 80% of the particles were between 12 2 and 44 0 ⁇ m
  • the residual methylene chloride and methanol in the microspheres was undetectable (less than 20 ppm)
  • Example 4 In this example, a homopolymer of polylactic acid was used 8 75 g polylactic acid (R202H from Boehringer Ingelheim) having an inherent viscosity of 0 18 dL/g was dissolved in 20 g dichloromethane Drug solution was prepared by dissolving 1.25 g leuprolide in 4 g methanol The polymer and the drug solutions were mixed to form the DP, which appeared as a homogeneous, nearly colorless solution The microspheres were prepared and harvested as disclosed in Example 1 using 5000 mL of continuous phase These microspheres had a drug incorporation efficiency of 85% and a drug load of 10 58% Microscope analysis showed that the microspheres had perfect spherical geometry, with most of the spheres appearing non-porous A few of the larger particles appeared to have pores at the center of the core The bulk density of the microspheres was 0 615 g/mL The particle size analysis showed that 50% of the particles were below 16 0 ⁇ m (volume distribution), and 80% of the
  • Example 5 the microspheres were prepared as in Example 1 using 8 75 g RG503H, 1 25 g leuprolide, 45 g methylene chloride and 10 7 g methanol for the DP
  • the stirring speed was increased to 9000 rpm, using 5000 mL CP of 0 35% PVA solution
  • the drug incorporation efficiency was 70 7% and the drug load was 8 84% in the microspheres
  • Microscope analysis showed that the microspheres were smaller, had a spherical geometry, and were predominantly non-porous
  • the bulk density of the microspheres was 0 510 g/mL
  • the particle size distribution analysis showed that
  • the microspheres contained 47 ppm residual methylene chloride and an undetectable amount of methanol (less than 10 ppm)
  • Example 6 microspheres were prepared containing a proteinaceous agent
  • the active agent was the protein Human Serum Albumin
  • the microspheres were prepared by forming a w/o/w emulsion using RG503H polymer
  • the preparation procedure was the same as in Example 1 except that the dispersed phase was formed by preparing a polymer solution of 8 75 g polymer in 45 g methylene chloride 5 mL of 25% w/v solution of human serum albumin was added slowly into polymer solution while stirring using a magnetic stirrer The dispersed phase thus obtained was stirred vigorously for about 5 minutes to form a milky white fine suspension
  • the microspheres were prepared as in Example 1 except that the stirring speed of the
  • Silverson unit was 6000 rpm The microspheres were harvested and freeze dried as in Example 1
  • microscope analysis showed that the microspheres had perfectly spherical geometry and were highly porous
  • the bulk density of the microspheres was 0 03 g mL
  • the particle size distribution analysis showed that 50% of the particles were below 48 4 ⁇ m, and 80% were between 23 0 and 69 7 ⁇ m
  • the microspheres did not have any detectible residual methylene chloride
  • Example 7 microspheres were prepared from RG503H and a non-peptide drug
  • the polymer solution was prepared by dissolving 8 74 g RG503H in 45 g dichloromethane 1.25 g dipyridamole was added slowly to the polymer solution and 2.53 g methanol was added to make the homogeneous solution, which appeared bright yellow 5000 mL of 0.35% PVA solution was used as the continuous phase
  • the microspheres were prepared, harvested and freeze dried as in Example 1 These microspheres had an 88% drug incorporation efficiency with an 1 1 0% drug load
  • Microscope analysis showed that the microspheres were spherical, generally smaller and predominantly non-porous
  • the bulk density of the microspheres was 0 45 g/mL
  • the particle size distribution analysis showed that 50% of the particles were below 13 5 ⁇ m (volume distribution), and 80% of the particles were between 5 8 and 20 0 ⁇ m
  • the microspheres had 107 ppm residual methylene chloride and
  • Example 8 As illustrated by this example, a significant advantage of the preferred continuous flow process according to the invention is the homogeneity of the drug distributed throughout the polymer matrix and the low porosity obtained for each microsphere
  • the microspheres were prepared according to the process of Example 1 using 9 20 g RG503H, 2 16 g Leuprolide, 41 4 g methylene chloride and 12 0 g methanol for the DP
  • the stirring speed was 7000 rpm using 4000 mL CP of 0 35% PVA solution
  • the drug incorporation efficiency was 73 7% and the drug load was 16 12% in the microspheres
  • the microspheres demonstrated a release profile with an initial burst
  • the average particle size was about 17 2 microns
  • the microspheres were prepared, harvested and freeze dried as in Example 1
  • the microspheres were cross-sectioned to a thickness of about 60nm and photomicrographed by transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • the pores were physically counted from at least three different randomly selected microspheres and averaged.
  • the percent area of the pores within the microsphere were measured by placing a transparent graph sheet over the TEM micrographs. The area occupied by each pore within the graphic boundary was measured and added together.
  • the percent area of the pores were determined from a ratio of the total pore area to the microsphere cross sectional area within the graphical boundary to give a numerical value for cross sectional porosity. Further evaluation revealed that the pores were bubbles or voids within the microspheres. It is believed that the pores result from the rapid removal of solvent.
  • the average number and size of polypeptide particles in a particular unit area of the microspheres are substantially the same as a second average number and size of particles in a different unit area of the microspheres.
  • the unit areas measured were of the same dimension.
  • the leuprolide active agent within the microsphere were found to be homogeneously distributed within the microspheres.
  • the microspheres were treated with a rabbit antibody double stain specific for leuprolide and labeled with gold.
  • the technique is readily known to those skilled in the art and is capable of detecting a single molecule of leuprolide.
  • TEM analysis showed that the leuprolide labelled with gold were homogeneously distributed throughout each microsphere and that the average number and size of the polypeptide particles were uniform in size.
  • Table II shows the average number of pores per microsphere and % pore area after cross sectional analysis.
  • Comparative Example 1 In this comparative example, leuprolide acetate microcapsules sold under the trade name LUPRON 7 5 were analyzed by the methods disclosed in Example 8 The average microcapsule size was about 20 um The following Table III shows the results obtained for microcapsules produced by this process.
  • microspheres were treated with a rabbit antibody double stain specific for leuprolide and labelled with gold TEM analysis showed that no specific leuprolide staining was observed This suggests that the leuprolide in these microcapsules were located in the pores and diffused or dissolved in the sectioning medium prior to staining. The pores were found to be irregular and nonuniformly distributed within the microcapsules

Abstract

Procédé continu servant à préparer des microsphères contenant un agent actif et présentant une porosité moyenne inférieure à 5 % de la totalité de leur section transversale. Ces microsphères permettent de libérer efficacement un agent actif à une vitesse constante et extrêmement régulière dans le milieu physiologique environnant. Elles sont composées d'un homopolymère d'acide lactique ou d'un copolymère d'acides glycolique et lactique. Un agent actif est réparti de façon homogène à l'intérieur d'une matrice constituée par l'homopolymère ou le copolymère, ce qui signifie que la quantité et la dimension moyennes de cet agent actif dans une zone déterminée sont sensiblement égales aux autres quantité et dimension de l'agent actif dans une autre zone de la microsphère.
PCT/US2000/021038 1999-08-04 2000-08-02 Microspheres presentant une liberation lente WO2001010414A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65104/00A AU6510400A (en) 1999-08-04 2000-08-02 Slow release microspheres

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36699599A 1999-08-04 1999-08-04
US09/366,995 1999-08-04

Publications (1)

Publication Number Publication Date
WO2001010414A1 true WO2001010414A1 (fr) 2001-02-15

Family

ID=23445507

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/021038 WO2001010414A1 (fr) 1999-08-04 2000-08-02 Microspheres presentant une liberation lente

Country Status (2)

Country Link
AU (1) AU6510400A (fr)
WO (1) WO2001010414A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6830737B2 (en) 2000-09-27 2004-12-14 Alkermes Controlled Therapeutics Inc. Ii Apparatus for preparing microparticles using liquid-liquid extraction
WO2006010155A2 (fr) 2004-07-16 2006-01-26 Oakwood Laboratories, L.L.C Antagonistes de l'hormone de liberation de la gonadotropine
GB2474402A (en) * 2008-07-31 2011-04-13 Univ Arkansas Preparation method of biodegradable micro particles containing drugs
WO2012025899A1 (fr) 2010-08-26 2012-03-01 Dominó - Indústrias Cerâmicas Sa Couche à base de silice à libération lente de parfum, carreau de céramique et leur procédé de production
US8921326B2 (en) 2006-12-18 2014-12-30 Takeda Pharmaceutical Company Limited Sustained-release composition and method for producing the same
WO2015149820A1 (fr) * 2014-03-31 2015-10-08 Pharmathen S.A. Préparation de microsphères de plga chargées en peptides ayant des caractéristiques de libération contrôlée
US9877478B2 (en) 2009-02-13 2018-01-30 Monsanto Technology Llc Encapsulation of herbicides to reduce crop injury
US9913469B2 (en) 2010-08-18 2018-03-13 Monsanto Technology Llc Early applications of encapsulated acetamides for reduced injury in crops
US11129381B2 (en) 2017-06-13 2021-09-28 Monsanto Technology Llc Microencapsulated herbicides
US11140900B2 (en) 2014-01-27 2021-10-12 Monsanto Technology Llc Aqueous herbicidal concentrates
CN113855810A (zh) * 2021-09-22 2021-12-31 西安纳瑞工控科技有限公司 一种药用辅料聚苯乙烯磺酸钠微球及其制备方法
US11419331B2 (en) 2019-01-30 2022-08-23 Monsanto Technology Llc Microencapsulated acetamide herbicides
CN115551485A (zh) * 2020-05-08 2022-12-30 M技术株式会社 均匀分散有生理活性物质的微球及含有其的缓释制剂
US20230173015A1 (en) * 2021-12-03 2023-06-08 Inventage Lab Inc. Microparticles containing leuprolide and method for producing the same
EP4147722A4 (fr) * 2020-05-08 2023-11-29 M. Technique Co., Ltd. Microsphères contenant un agent primaire dispersé de manière uniforme et préparation à libération prolongée comprenant des microsphères contenant un agent primaire dispersé de manière uniforme

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5395916A (en) * 1991-09-06 1995-03-07 Teijin Limited Biodegradable copolymer from hydroxy proline
WO1995035097A1 (fr) * 1994-06-18 1995-12-28 University Of Nottingham Microparticules de polymere destinees a l'apport des medicaments
US5540937A (en) * 1992-07-27 1996-07-30 Rhone Merieux Process for preparing microspheres for the prolonged release of the LHRH hormone and its analogues, microspheres and formulations obtained
US5980948A (en) * 1996-08-16 1999-11-09 Osteotech, Inc. Polyetherester copolymers as drug delivery matrices

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5395916A (en) * 1991-09-06 1995-03-07 Teijin Limited Biodegradable copolymer from hydroxy proline
US5540937A (en) * 1992-07-27 1996-07-30 Rhone Merieux Process for preparing microspheres for the prolonged release of the LHRH hormone and its analogues, microspheres and formulations obtained
WO1995035097A1 (fr) * 1994-06-18 1995-12-28 University Of Nottingham Microparticules de polymere destinees a l'apport des medicaments
US5980948A (en) * 1996-08-16 1999-11-09 Osteotech, Inc. Polyetherester copolymers as drug delivery matrices

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6884372B2 (en) 2000-09-27 2005-04-26 Alkermes Controlled Therapeutics, Inc. Ii Method for preparing microparticles using liquid-liquid extraction
US6830737B2 (en) 2000-09-27 2004-12-14 Alkermes Controlled Therapeutics Inc. Ii Apparatus for preparing microparticles using liquid-liquid extraction
WO2006010155A2 (fr) 2004-07-16 2006-01-26 Oakwood Laboratories, L.L.C Antagonistes de l'hormone de liberation de la gonadotropine
EP1778278A2 (fr) * 2004-07-16 2007-05-02 Oakwood Laboratories L.L.C. Antagonistes de l'hormone de liberation de la gonadotropine
EP1778278A4 (fr) * 2004-07-16 2010-02-03 Oakwood Lab L L C Antagonistes de l'hormone de liberation de la gonadotropine
US8329863B2 (en) 2004-07-16 2012-12-11 Oakwood Laboratories, Llc Gonadotropin releasing hormone antagonists
US9617303B2 (en) 2006-12-18 2017-04-11 Takeda Pharmaceutical Company Limited Sustained-release composition and method for producing the same
US8921326B2 (en) 2006-12-18 2014-12-30 Takeda Pharmaceutical Company Limited Sustained-release composition and method for producing the same
US9713595B2 (en) 2006-12-18 2017-07-25 Takeda Pharmaceuticals Company Limited Sustained-release composition and method for producing the same
GB2474402A (en) * 2008-07-31 2011-04-13 Univ Arkansas Preparation method of biodegradable micro particles containing drugs
GB2474402B (en) * 2008-07-31 2011-06-29 Univ Arkansas Preparation method of biodegradable micro-particles containing drugs
US9877478B2 (en) 2009-02-13 2018-01-30 Monsanto Technology Llc Encapsulation of herbicides to reduce crop injury
US10813352B2 (en) 2009-02-13 2020-10-27 Monsanto Technology Llc Encapsulation of herbicides to reduce crop injury
US11412734B2 (en) 2010-08-18 2022-08-16 Monsanto Technology Llc Early applications of encapsulated acetamides for reduced injury in crops
US9913469B2 (en) 2010-08-18 2018-03-13 Monsanto Technology Llc Early applications of encapsulated acetamides for reduced injury in crops
WO2012025899A1 (fr) 2010-08-26 2012-03-01 Dominó - Indústrias Cerâmicas Sa Couche à base de silice à libération lente de parfum, carreau de céramique et leur procédé de production
US11140900B2 (en) 2014-01-27 2021-10-12 Monsanto Technology Llc Aqueous herbicidal concentrates
JP2017509661A (ja) * 2014-03-31 2017-04-06 ファーマシェン エス．エー． 徐放特性を持つペプチド充填ｐｌｇａミクロスフェアの調製
KR20160137608A (ko) * 2014-03-31 2016-11-30 파마덴 에스.에이. 제어된 방출 특성을 갖는 펩티드 적재된 plga 마이크로스피어의 제조방법
WO2015149820A1 (fr) * 2014-03-31 2015-10-08 Pharmathen S.A. Préparation de microsphères de plga chargées en peptides ayant des caractéristiques de libération contrôlée
US9943483B2 (en) 2014-03-31 2018-04-17 Pharmathen S.A. Preparation of peptide loaded PLGA microspheres with controlled release characteristics
EA032580B1 (ru) * 2014-03-31 2019-06-28 Фарматен С.А. Способ получения загруженных октреотид ацетатом микросфер на основе plga с характеристиками контролированного высвобождения
KR102218655B1 (ko) * 2014-03-31 2021-02-22 파마덴 에스.에이. 제어된 방출 특성을 갖는 펩티드 적재된 plga 마이크로스피어의 제조방법
CN106170284A (zh) * 2014-03-31 2016-11-30 法尔玛赞公司 具有控释特征的装载肽的plga微球体的制备
US11129381B2 (en) 2017-06-13 2021-09-28 Monsanto Technology Llc Microencapsulated herbicides
US11937599B2 (en) 2017-06-13 2024-03-26 Monsanto Technology Llc Microencapsulated herbicides
US11419331B2 (en) 2019-01-30 2022-08-23 Monsanto Technology Llc Microencapsulated acetamide herbicides
CN115551485A (zh) * 2020-05-08 2022-12-30 M技术株式会社 均匀分散有生理活性物质的微球及含有其的缓释制剂
EP4147722A4 (fr) * 2020-05-08 2023-11-29 M. Technique Co., Ltd. Microsphères contenant un agent primaire dispersé de manière uniforme et préparation à libération prolongée comprenant des microsphères contenant un agent primaire dispersé de manière uniforme
EP4147721A4 (fr) * 2020-05-08 2023-11-29 M. Technique Co., Ltd. Microsphère ayant une substance physiologiquement active dispersée uniformément dans celle-ci, et préparation à libération prolongée contenant celle-ci
CN113855810A (zh) * 2021-09-22 2021-12-31 西安纳瑞工控科技有限公司 一种药用辅料聚苯乙烯磺酸钠微球及其制备方法
US20230173015A1 (en) * 2021-12-03 2023-06-08 Inventage Lab Inc. Microparticles containing leuprolide and method for producing the same

Also Published As

Publication number Publication date
AU6510400A (en) 2001-03-05

Similar Documents

Publication Publication Date Title
EP0994695B1 (fr) Methode de production de microspheres en continu
Shiga et al. Preparation of poly (D, L‐lactide) and copoly (lactide‐glycolide) microspheres of uniform size
JP4903344B2 (ja) 選択ポリマー分子量を有するマイクロ粒子を調製する方法
WO2001010414A1 (fr) Microspheres presentant une liberation lente
Ravivarapu et al. Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres
AU746337B2 (en) Methods for fabricating polymer-based controlled release preparations
US6479065B2 (en) Process for the preparation of polymer-based sustained release compositions
US20180177785A1 (en) Method of Making Sustained Release Microparticles
US6506410B1 (en) Sustained release microparticle and method for preparing the same
AU772910B2 (en) Method of producing submicron particles of a labile agent
EP2803351B1 (fr) Procédé continu de préparation de microsphères
US6296842B1 (en) Process for the preparation of polymer-based sustained release compositions
US20090104274A1 (en) Process of making microspheres
EP2283821A1 (fr) Préparation des microparticules biodégradables contenant un agent biologiquement actif
KR20000010697A (ko) 미립자
JP5733981B2 (ja) ポリマー微粒子を調製する方法及びデバイス
CN1187134A (zh) 非凝集体促红细胞生成素的延续释放组合物
EP2334288B1 (fr) Procédé de micro-encapsulation avec un solvant et un sel
CA2540771A1 (fr) Agents therapeutiques nanoparticulaires biologiquement actifs
JP2002542184A (ja) 水溶性物質のマイクロカプセル化方法
WO1998007412A1 (fr) Microparticules a liberation lente contenant une substance hydrophobe
EP1210942B1 (fr) Microparticules
JP2867404B2 (ja) ドラッグデリバリーのための多孔性ミクロスフェアおよびその製造法
US9539213B2 (en) Method of preparing microspheres by using polymer having sol-gel transition property and microspheres prepared thereby
Sohier et al. Release of small water-soluble drugs from multiblock copolymer microspheres: a feasibility study

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WA Withdrawal of international application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WA Withdrawal of international application