WO1998027963A2 - Gel composition and methods - Google Patents

Gel composition and methods Download PDF

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Publication number
WO1998027963A2
WO1998027963A2 PCT/US1997/023659 US9723659W WO9827963A2 WO 1998027963 A2 WO1998027963 A2 WO 1998027963A2 US 9723659 W US9723659 W US 9723659W WO 9827963 A2 WO9827963 A2 WO 9827963A2
Authority
WO
WIPO (PCT)
Prior art keywords
beneficial agent
solvent
composition
polymer
gel
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/US1997/023659
Other languages
English (en)
French (fr)
Other versions
WO1998027963A3 (en
Inventor
Kevin J. Brodbeck
Ann T. Gaynor-Duarte
Theodore T. Shen
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.)
Alza Corp
Original Assignee
Alza Corp
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
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21870398&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1998027963(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to KR1019997005514A priority Critical patent/KR100616793B1/ko
Priority to NZ335851A priority patent/NZ335851A/en
Priority to HK00103307.2A priority patent/HK1023950B/xx
Priority to IL13053297A priority patent/IL130532A0/xx
Priority to JP52902098A priority patent/JP4642946B2/ja
Application filed by Alza Corp filed Critical Alza Corp
Priority to EP97952575A priority patent/EP0959873B1/en
Priority to CA2275525A priority patent/CA2275525C/en
Priority to AU56154/98A priority patent/AU739469B2/en
Priority to DE69735384T priority patent/DE69735384T2/de
Publication of WO1998027963A2 publication Critical patent/WO1998027963A2/en
Publication of WO1998027963A3 publication Critical patent/WO1998027963A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • A61K9/0019—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • the present invention relates to a gel composition that can be
  • the present invention also relates to methods of
  • Biodegradable polymers have been used for many years in medical
  • glycolide based upon glycolide, lactide, caprolactone, and copolymers thereof.
  • the biodegradable polymers can be thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials which are thermoplastic materials
  • thermoplastic and thermosetting biodegradable polymers are thermoplastic and thermosetting biodegradable polymers
  • sutures, clips, and staples are all sutures, clips, and staples.
  • the material be molded or flow to fill voids or cavities where it may be
  • o biodegradable polymers also often are or have to be formed outside the
  • the drug is incorporated into the polymer and the
  • the drug delivery system has to be
  • One reservoir device having a rate-controlling membrane and zero-
  • 1 materials may or may not contain a drug which can be released into the body.
  • microspheres, or microcapsules are poorly retained because of their small
  • microcapsule or small-particle system one other major limitation of the microcapsule or small-particle system is their lack of reversibility without extensive surgical intervention. That is, if there
  • microparticles or microcapsulation limitation on microparticles or microcapsulation is the difficulty in
  • thermoplastic system is used wherein a non-
  • thermosetting system is used
  • the systems provide a syringeable, solid biodegradable delivery
  • compositions that utilize solvents which are miscible to dispersible in water,
  • the polarity of the solvents ⁇ is described as being effective to provide about at least 10% solubility in
  • the polymer matrix systems are described as forming a porous core
  • composition comprises
  • composition can take the
  • o composition can contain surfactants, flavoring agents, viscosity controlling
  • one of the examples is polyethylene glycol 400.
  • plasticizers in an amount up to about 30 wt %, for local application
  • plasticizers listed are, inter alia,
  • compositions which are modified by plasticizers consisting of various partial esters of citric acid.
  • solvent/plasticizers that are very or relatively soluble in aqueous body fluids to
  • beneficial agent that is manifested by an initial, rapid release of beneficial
  • agents such as hormones and the like, in the body of the subject being
  • modulating agents such as metal salts as described in U.S. Patents
  • compositions comprised of a polymer dissolved in a solvent, another problem
  • composition solidifies slowly after injection as
  • compositions are relatively non-viscous in order to be injected, a large
  • composition is released within one day of the initial injection.
  • finger-like pores are open at the surface of the implant to the environment of
  • the finger-like pores allow very rapid uptake of aqueous body
  • beneficial agent are shut off from contact with the body fluids and a significant
  • lag time That lag time is undesirable from the standpoint of presenting a controlled, sustained release of beneficial agent to the subject
  • the present invention provides a method and an implantable system
  • the invention provides a method of preparing implant systems
  • the invention comprises a method of administering
  • a beneficial agent to a subject which comprises
  • the beneficial agent will be released within the first 24 hours after
  • the invention comprises a method of systemically
  • administering a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dispersed or dissolved substantially
  • the invention comprises a method of
  • interior of the polymer gel is above that required to saturate the beneficial
  • the invention comprises an implantable,
  • biodegradable composition for the systemic delivery of a beneficial agent to a
  • composition comprises a polymer; an amount of a solvent
  • the solvent comprises a single solvent or a
  • the present invention comprises an implantable,
  • biodegradable composition for the sustained delivery of a beneficial agent to
  • composition comprises a polymer; an effective
  • the mixture comprises a mixture of solvents with at least one solvent in the mixture ⁇ having a miscibility in water of less than 7% by weight.
  • the solvent in the mixture ⁇ having a miscibility in water of less than 7% by weight.
  • the invention comprises an implantable
  • composition comprises a polymer; an effective plasticizing
  • the present invention provides an implantable gel
  • R ⁇ is lower alkyl, aryl or aralkyl and R 2 is aralkyl or lower alkyl;
  • R ⁇ and R 2 may be the same or different; with the proviso that when R ⁇ and R 2 are
  • each lower alkyl the number of total carbon atoms represented by R ⁇ and R 2
  • the present invention provides an implantable gel
  • composition comprising:
  • the polymer the solvent having a miscibility in water of less than 7% by
  • the solvent will have a miscibility in water of 6% or less by
  • the present invention provides a method of
  • the present invention provides a method of
  • the invention provides a gel composition
  • composition has a burst index of less than 8.
  • the invention comprises a kit for administration
  • the invention comprises an implantable
  • composition for the systemic delivery of a beneficial agent comprising a
  • cDNA selected from the group consisting of cDNA, DNA, peptides, proteins and
  • composition having a burst index of 8
  • the invention comprises an implantable composition
  • a beneficial agent comprising a poly(lactide-co-
  • the polymer ; and a beneficial agent.
  • the invention comprises an implantable
  • composition comprising a viscous gel and a beneficial agent dispersed or ⁇ dissolved therein, wherein the viscous gel maintains a glass transition
  • the invention comprises a method of
  • the system having a burst index of 8 or less.
  • the invention comprises an implantable system
  • Figure 1 is a graph illustrating the dispense force required to dispense
  • Figure 2 is a graph illustrating the in vitro release profiles of lysozyme
  • Figure 3 is a graph illustrating the viscosity profiles of emulsions at
  • Figures 4A and 4B are graphs illustrating the degree of water uptake
  • Figures 5A and 5B are graphs of in vivo release rate profiles of non-
  • the present invention is directed to a method of systemically or locally
  • implantable system formed as a viscous gel from a biocompatible polymer
  • a solubility modulator of the beneficial agent is present in the system.
  • the implant systems useful in this invention will release, in the first
  • the viscous gel formed preferably
  • Water uptake and burst may be controlled by using polymer-solvent
  • compositions wherein the solvent is substantially immiscible in water, i.e., less
  • beneficial agent and the sustained delivery of beneficial agent.
  • the sustained delivery of beneficial agent Generally, the
  • compositions of the invention will be gel-like and will form with a substantially
  • hardened implant may maintain a rubbery (non-rigid) composition with the
  • composition when the composition is intended for implantation by injection,
  • the viscosity optionally may be modified by emulsifiers to obtain a gel
  • composition having a viscosity low enough to permit passage of the gel
  • the beneficial agent may be added to the implant systems to provide
  • modulator to the implant system may enable the use of a solvent having a
  • the implant system utilize at least one solvent having a
  • mixtures of solvents which include a solvent having 7% or less by weight
  • solubility in water and one or more miscible solvents optionally having
  • AUC means the area under the curve obtained from an in
  • burst index means, with respect to a particular composition
  • the quotient formed by dividing (i) the AUC calculated for the first twenty-four hours after implantation
  • systemic means, with respect to delivery or administration
  • beneficial agent is detectable at a
  • beneficial agent to a subject, that beneficial agent is delivered to a localized
  • gel vehicle means the composition formed by mixture of the
  • Prolonged period means a period of time over which
  • initial burst means, with respect to a particular composition
  • the initial burst may vary depending on the shape and surface area of the
  • solubility modulator means, with respect to the beneficial
  • agent an agent that will alter the solubility of the beneficial agent
  • the modulator may enhance or retard the
  • solubility modulator will be described in detail below.
  • beneficial agent itself, such as by the formation of complexes, or with both.
  • solubility modulator is “associated" with
  • Solubility modulators may be mixed with the beneficial agent prior
  • subject means, with respect to the administration of a
  • composition of the invention an animal or a human being.
  • miscible means that 7% or less by weight of the solvent is soluble in or
  • the environment of use is a fluid environment and may
  • Polymers that may be useful in the invention may be biodegradable
  • polycaprolactones polyanhydrides, polyamines, polyurethanes,
  • polyesteramides polyorthoesters, polydioxanones, polyacetals, polyketals,
  • polycarbonates polyorthocarbonates, polyphosphazenes, succinates,
  • polystyrene resin that is, a lactic acid-
  • based polymer that can be based solely on lactic acid or can be a copolymer
  • lactic acid includes the isomers L-lactic acid, D-lactic acid,
  • DL-lactic acid and lactide while the term "glycolic acid” includes glycolide.
  • poly(lactide-co-glycolide)copolymers commonly referred to as poly(lactide-co-glycolide)copolymers
  • the polymer may have a monomer ratio of lactic acid/glycolic
  • an especially useful copolymer has a monomer ratio of lactic
  • the lactic acid-based polymer has a number average molecular weight
  • the polymer can be prepared in
  • the lactic acid-based polymer can be prepared directly from lactic acid or a
  • lactic acid-based polymers are available commercially. For instance, 50:50 lactic acid:glycolic acid copolymers having molecular weights of 5,000,
  • the biocompatible polymer is present in the gel composition in an
  • the viscous gel comprising the combined amounts of the biocompatible
  • the solvent will be added to polymer in amounts
  • the solvent must be biocompatible, should form a viscous gel with the
  • the solvent may be a
  • water i.e., having a solubility in water of less than 7% by weight.
  • the solvents are five weight percent or less soluble in water; more preferably
  • solvent in water is equal to or less than 0.5 weight percent.
  • Water miscibility may be determined experimentally as follows: Water
  • solvent/water mixture when solvent mixtures are used, for example 20%
  • Solvents useful in this invention are generally less than 7% water
  • parameter may be selected from the lower alkyl and aralkyl esters of aryl
  • acids such as benzoic acid, the phthalic acids, salicylic acid, lower alkyl
  • esters of citric acid such as triethyl citrate and tributyl citrate and the like, and
  • aryl, aralkyl and lower alkyl ketones are those
  • R ⁇ is aryl or aralkyl
  • R 2 is lower alkyl or aralkyl
  • R and R 2 are
  • R, and R 2 are lower alkyl, the total carbon atoms in R, and R 2 combined are 4 or more,
  • lower alkyl means straight or branched chain hydrocarbons
  • aralkyl means (lower alkyl)phenyl, e.g., benzyl, phenethyl, 1-
  • aryl means phenyl, optionally substituted by non-
  • requisite solubility may be selected include: 1 ,4-cyclohexane dimethanol
  • dibenzoate diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzo
  • glycol benzoate and dipropylene glycol benzoate blend polyethylene glycol
  • requisite solubility may be selected include: Alkyl benzyl phthalate, bis-
  • dimethyl phthalate diethyl phthalate, dibutyl phthalate, diisobutyl phthalate,
  • dicapryl phthalate dicapryl phthalate, mixed alcohol phthalate, di-(2-ethylhexyl) phthalate, linear
  • Preferred solvents include the lower alkyl and aralkyl esters of the aryl
  • acids described above are benzoic acid and the
  • phthalic acids such as phthalic acid, isophthalic acid, and terephathalic acid.
  • Most preferred solvents are derivatives of benzoic acid and include, but are
  • Preferred solvent mixtures are those in
  • Especially preferred mixtures are those of 80/20 mixtures by weight of benzyl
  • having a miscibility in water of less than 7% by weight may be mixed with one
  • component solvents or more additional miscible solvents.
  • Component solvents or more additional miscible solvents.
  • solvents compatible and miscible with the primary solvent may have a higher
  • component solvent mixtures Useful component solvent mixtures may be selected from any suitable component solvent mixtures.
  • Useful component solvent mixtures may be selected from any suitable component solvent mixtures.
  • component solvent mixtures having a
  • component solvents useful in component solvent mixtures are those
  • triacetin examples include, but are not limited, to triacetin, diacetin, tributyrin, triethyl citrate,
  • silicone fluid glylcerin, ethylene glycol, polyethylene glycol, octanol, ethyl
  • lactate propylene glycol
  • propylene carbonate ethylene carbonate
  • butyrolactone ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-
  • the primary solvent is selected from
  • acid based polymer most preferably PLGA, having a number average
  • the most preferred solvents are benzyl benzoate and the
  • lower alkyl esters of benzoic acid may be used.
  • miscible solvents e.g., triacetin
  • Implants are prepared as viscous gels in which the beneficial agent is
  • compositions are dissolved or dispersed substantially throughout, and such compositions are
  • benzoic acid provides increased control of water migration resulting in increased stability of beneficial agent.
  • compositions may provide viscous gels that have a glass transition
  • the solvent or solvent mixture is capable of dissolving the polymer to
  • compositions of the present invention provide implants having a
  • NMP N-methyl-2-pyrrolidone
  • Implants with benzyl benzoate take up the least water, whether compared to
  • Figure 4B provides a comparison of various solvents alone
  • Gel compositions of this invention may take up 25 % or
  • agents that modulate the water solubility of the beneficial agent can also be used.
  • Burst indices and percent of beneficial agent released in the first twenty-four ⁇ hours after implantation may be reduced by one-third to two-thirds or more by the use of
  • solubility modulators associated with the beneficial agent.
  • Such modulators are typically
  • beneficial agent such as metallic ions, other stabilizing agents, waxes, lipids, oils, non-
  • solubility modulators may permit the use of
  • release will be not greater than 15% and more preferably
  • compositions such modulators would be necessary.
  • interferons including interferon alpha-
  • Such agents may be, for example, sugars and the like, and are well known in the art. finger-like pores in the surface of implants formed using prior art processes.
  • composition of the present invention takes the form of a
  • the implant being much the same as the pores on the surface of the implant.
  • compositions of the present invention retain their gel-like consistency over a
  • present invention generally have a glass transition temperature, T g , of less
  • body temperature of the subject e.g. 37 0 C for humans.
  • pores extending from the surface into the interior of the implant being open at
  • the surface of the implant Furthermore, the surface pores offer only a limited
  • the viscosity optionally may be modified by the
  • duration of the delivery period is relatively short, e.g., less than 7-14
  • compositions of the present invention intended for
  • 3 systemic delivery may provide a gel composition having a burst index of 8 or
  • compositions of PLGA with solvents having a miscibility in water of less are less.
  • compositions intended for local delivery of beneficial agent are formed
  • compositions of the present invention will have initial bursts of 20% or less
  • Implant systems having initial bursts of 5% or less.
  • implants of the invention containing chemotherapeutic agents are
  • ie agents may exhibit toxic side effects when administered systemically.
  • the solvent or solvent mixture is typically present in an amount of from
  • viscous gel i.e., the combined amounts of the polymer and the solvent.
  • viscous gel formed by mixing the polymer and the solvent typically exhibits a
  • composition being prepared. Since it is often desirable to administer the composition
  • agent composition have sufficiently low viscosity in order to permit it to be
  • compositions should have
  • polymer composition is to be administered as an injectable gel
  • the level of polymer dissolution will need to be balanced with the resulting gel ⁇ viscosity, to permit a reasonable force to dispense the viscous gel from a
  • an emulsifying agent may optionally be added to the composition.
  • the emulsifying agent forms a separate
  • the continuous phase composed of dispersed droplets of microscopic size that typically have an average diameter of less than about 100 microns.
  • agent elongate in the direction of shear and substantially decrease the
  • a viscous gel having a viscosity of from about 5,000 to about
  • the emulsifying agent typically is present in an amount
  • gel composition that is the combined amounts of polymer, solvent,
  • Emulsifying agents include, for example, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite
  • solvents that are not fully miscible with the polymer solvent are not fully miscible with the polymer solvent
  • Illustrative emulsifying agents are water, alcohols, polyols,
  • esters carboxylic acids, ketones, aldehydes and mixtures thereof. Preferred
  • emulsifying agents are alcohols, propylene glycol, ethylene glycol, glycerol,
  • emulsifying agent affects the size of the dispersed droplets. For instance,
  • ethanol will provide droplets that have average diameters that can be on the order of ten times larger than the droplets obtained with an isotonic saline
  • FIG. 3 shows the viscosities at different shear rates using water
  • the emulsifying agent does not constitute a
  • composition of the present invention can be formulated to avoid the burst
  • the emulsifying agent has little impact on the release properties of
  • the implant systems of the present invention preferably are
  • the implant will be administered as a leave-behind product, it may be
  • Such applications may permit loading of beneficial agent in
  • the beneficial agent can be any physiologically or pharmacologically
  • antioxidants antioxidants, stabilizing agents, permeation enhancers, etc. that do not
  • the beneficial agent may be any of the agents
  • agents include drug agents, medicaments, vitamins,
  • Drug agents which may be delivered by the present invention include
  • agents may be selected from, for example, proteins, enzymes, hormones,
  • polynucleotides polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, ⁇ polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-
  • procainamide hydrochloride amphetamine sulfate, methamphetamine
  • cortisone acetate cortisone acetate, dexamethasone and its derivatives such as
  • betamethasone triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl
  • norethindrone norethisterone, norethiederone, progesterone, norgesterone
  • norethynodrel aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol,
  • alprenolol cimetidine, clonidine, imipramine, levodopa, chlorpromazine,
  • ketoprofen ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac,
  • ferrous lactate ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem,
  • nimodipine nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine,
  • captopril ramipril, famotidine, nizatidine, sucralfate, etintidine, tetratolol,
  • proteins and peptides which include, but are not limited to,
  • bone morphogenic proteins insulin, colchicine, glucagon, thyroid stimulating
  • hormone parathyroid and pituitary hormones, calcitonin, renin, prolactin,
  • corticotrophin corticotrophin, thyrotropic hormone, follicle stimulating hormone, chorionic
  • gonadotropin gonadotropin releasing hormone, bovine somatotropin, porcine
  • pancreozymin pancreozymin, luteinizing hormone, LHRH, LHRH agonists and antagonists
  • interferons such as interferon alpha-2a, interferon alpha-2b, and
  • hormone and its derivatives such as methione-human growth hormone and its derivatives such as methione-human growth hormone and
  • promoters growth factors such as insulin-like growth factor, coagulation factors, human pancreas hormone releasing factor, analogs and derivatives
  • the present invention also finds application with chemotherapeutic
  • agents may be injected directly into the tumor tissue for sustained delivery of
  • the chemotherapeutic agent over time. In some cases, particularly after
  • the gel may be implanted directly into the resulting tumor
  • carboplatin carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecin, etopside,
  • cytokines cytokines, ribozymes, interferons, oligonucleotides and oligonucleotide
  • chemotherapeutic agents such as for example cisplatin and carboplatin and
  • the beneficial agent is preferably incorporated into the viscous gel
  • particles having an average particle size of about 5 microns For instance, particles having an average particle size of about 5 microns
  • low shear device such as a Ross double planetary mixer at
  • agent can be achieved substantially without degrading the beneficial agent.
  • the beneficial agent is typically dissolved or dispersed in the
  • composition in an amount of from about 1 to about 50% by weight, preferably
  • the overall gel composition i.e., polymer, solvent and beneficial
  • the beneficial agent will be any beneficial agent that will be any beneficial agent that will be any beneficial agent.
  • the beneficial agent will be any beneficial agent.
  • release rates on the order of from about 0.1 to about 100
  • micrograms/day preferably from about 1 to about 10 micrograms per day, for
  • beneficial agent may be controlled by adjusting the volume of the gel
  • composition during the first day is the composition during the first day.
  • FIGS 5A and 5B illustrate representative release profiles of human
  • hGH growth hormone
  • the benefits of benzyl benzoate are apparent in that comparison.
  • the hGH-benzyl benzoate implant shows a lower burst and a nearly zero
  • compositions they are desired or provide useful properties to the composition, such as
  • composition includes a peptide or a protein
  • solubility modulator that may, for example, be a solubility modulator
  • hGH for example, it is
  • a salt of a divalent metal preferably zinc.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Surgery (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Colloid Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Prostheses (AREA)
PCT/US1997/023659 1996-12-20 1997-12-18 Gel composition and methods Ceased WO1998027963A2 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
DE69735384T DE69735384T2 (de) 1996-12-20 1997-12-18 Gelzusammensetzungen und verfahren
CA2275525A CA2275525C (en) 1996-12-20 1997-12-18 Gel composition and methods
HK00103307.2A HK1023950B (en) 1996-12-20 1997-12-18 Gel composition and methods
IL13053297A IL130532A0 (en) 1996-12-20 1997-12-18 Gel composition and methods
JP52902098A JP4642946B2 (ja) 1996-12-20 1997-12-18 ゲル組成物および方法
KR1019997005514A KR100616793B1 (ko) 1996-12-20 1997-12-18 겔 조성물 및 방법
EP97952575A EP0959873B1 (en) 1996-12-20 1997-12-18 Gel composition and methods
NZ335851A NZ335851A (en) 1996-12-20 1997-12-18 Implantable biodegradable gel composition containing an active ingredient, a polymer and a solvent such that the polymer and the solvent form a gel
AU56154/98A AU739469B2 (en) 1996-12-20 1997-12-18 Gel composition and methods

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3343996P 1996-12-20 1996-12-20
US60/033,439 1996-12-20

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WO1998027963A3 WO1998027963A3 (en) 1998-10-15

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PCT/US1997/023341 Ceased WO1998027962A2 (en) 1996-12-20 1997-12-18 Injectable depot gel composition and method of preparing the composition

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US (6) US6130200A (enExample)
EP (2) EP0959873B1 (enExample)
JP (4) JP2002512597A (enExample)
KR (1) KR100616793B1 (enExample)
CN (1) CN1146402C (enExample)
AT (2) ATE318580T1 (enExample)
AU (2) AU5609798A (enExample)
CA (3) CA2591581C (enExample)
DE (2) DE69705746T2 (enExample)
DK (2) DK0959873T3 (enExample)
ES (2) ES2158611T3 (enExample)
GR (1) GR3036599T3 (enExample)
IL (1) IL130532A0 (enExample)
NZ (1) NZ335851A (enExample)
PT (2) PT949905E (enExample)
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AU5615498A (en) 1998-07-17
WO1998027962A2 (en) 1998-07-02
JP2010095544A (ja) 2010-04-30
CN1146402C (zh) 2004-04-21
ATE318580T1 (de) 2006-03-15
JP2010120952A (ja) 2010-06-03
US20030044467A1 (en) 2003-03-06
KR100616793B1 (ko) 2006-08-28
DE69735384T2 (de) 2006-08-10
CA2275525C (en) 2011-02-08
DK0959873T3 (da) 2006-07-03
DK0949905T3 (da) 2001-10-22
EP0959873B1 (en) 2006-03-01
US20020034532A1 (en) 2002-03-21
CA2591581A1 (en) 1998-07-02
US6130200A (en) 2000-10-10
EP0949905A2 (en) 1999-10-20
HK1020009A1 (en) 2000-03-10
JP2002512597A (ja) 2002-04-23
PT959873E (pt) 2006-07-31
GR3036599T3 (en) 2001-12-31
WO1998027963A3 (en) 1998-10-15
DE69735384D1 (de) 2006-04-27
IL130532A0 (en) 2000-06-01
CA2275525A1 (en) 1998-07-02
KR20000069564A (ko) 2000-11-25
US6468961B1 (en) 2002-10-22
WO1998027962A3 (en) 1998-10-01
ES2256898T3 (es) 2006-07-16
CA2591581C (en) 2013-01-29
NZ335851A (en) 2001-02-23
DE69705746D1 (de) 2001-08-23
AU739469B2 (en) 2001-10-11
EP0949905B1 (en) 2001-07-18
DE69705746T2 (de) 2001-10-31
HK1023950A1 (en) 2000-09-29
JP4642946B2 (ja) 2011-03-02
US6331311B1 (en) 2001-12-18
ATE203157T1 (de) 2001-08-15
AU5609798A (en) 1998-07-17
ES2158611T3 (es) 2001-09-01
US20060013879A9 (en) 2006-01-19
JP2001509146A (ja) 2001-07-10
CA2275587C (en) 2006-10-24
CA2275587A1 (en) 1998-07-02
PT949905E (pt) 2001-12-28
US6673767B1 (en) 2004-01-06
CN1240346A (zh) 2000-01-05
EP0959873A2 (en) 1999-12-01

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