US20070196416A1 - Pharmaceutical compositions with enhanced stability - Google Patents

Pharmaceutical compositions with enhanced stability Download PDF

Info

Publication number
US20070196416A1
US20070196416A1 US11/653,636 US65363607A US2007196416A1 US 20070196416 A1 US20070196416 A1 US 20070196416A1 US 65363607 A US65363607 A US 65363607A US 2007196416 A1 US2007196416 A1 US 2007196416A1
Authority
US
United States
Prior art keywords
acid
polymeric composition
peptide
peptide agent
injectable polymeric
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.)
Abandoned
Application number
US11/653,636
Other languages
English (en)
Inventor
Yuhua Li
Benjamin Chien
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.)
Foresee Pharmaceuticals Co Ltd
Original Assignee
QPS LLC
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
Priority to US11/653,636 priority Critical patent/US20070196416A1/en
Application filed by QPS LLC filed Critical QPS LLC
Priority to TW96110525A priority patent/TWI376241B/zh
Assigned to QUEST PHARMACEUTICAL SERVICES, LLC reassignment QUEST PHARMACEUTICAL SERVICES, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHIEN, BENJAMIN, LI, YUHUA
Publication of US20070196416A1 publication Critical patent/US20070196416A1/en
Assigned to QPS, LLC reassignment QPS, LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: QUEST PHARMACEUTICAL SERVICES, LLC
Assigned to CAPITALSOURCE CF LLC, AS AGENT reassignment CAPITALSOURCE CF LLC, AS AGENT SECURITY AGREEMENT Assignors: QPS, LLC
Assigned to QPS, LLC, BIO-KINETIC CLINICAL APPLICATIONS, LLC, QPS HOLDINGS, LLC reassignment QPS, LLC RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: CAPITALSOURCE CF LLC
Assigned to FORESEE PHARMACEUTICALS, LLC reassignment FORESEE PHARMACEUTICALS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: QPS, LLC
Assigned to FORESEEACER PHARMACEUTICALS, INC. reassignment FORESEEACER PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FORESEE PHARMACEUTICALS, LLC
Assigned to FORESEEACER PHARMACEUTICALS, INC. reassignment FORESEEACER PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FORESEE PHARMACEUTICALS, LLC
Assigned to FORESEE PHARMACEUTICALS CO., LTD. reassignment FORESEE PHARMACEUTICALS CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FORESEEACER PHARMACEUTICALS, INC.
Priority to US15/230,413 priority patent/US9572857B2/en
Priority to US15/406,321 priority patent/US9744207B2/en
Priority to US15/661,066 priority patent/US10251956B2/en
Priority to US16/376,028 priority patent/US10646572B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • 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
    • A61K38/2292—Thymosin; Related peptides
    • 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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • peptide agents such as peptides, oligopeptides, polypeptides, and proteins have been discovered and have received much attention as drug candidates.
  • many peptide agents are not stable as they are easily hydrolyzed or degraded in vivo by enzymes resulting in a very short circulation half-life. Therefore, most of peptide medicines have been administered by injection, typically multiple times per day.
  • peptide agents particularly hormones
  • it requires the drug to be delivered continuously at a controlled rate over a long period of time, and thus a controlled release delivery system is desirable.
  • Such systems may be provided by incorporating the peptide agents in biodegradable and biocompatible polymer matrices.
  • the polymer is dissolved in an organic solvent and then mixed with the peptide agents that is fabricated into the forms of microcapsules, microgranules or implantable rods by removing the organic solvent.
  • the peptide agent is entrapped within the polymer matrices.
  • the biodegradable polymer and the peptide agents are dissolved in a biocompatible organic solvent to provide a liquid composition.
  • the solvent dissipates into the surrounding aqueous environment, and the polymer forms a solid or gel depot from which the bioactive agent is released over a long period of time.
  • bioactive agent containing basic functional groups interacts with biodegradable polymer to catalyze (or expedite) the degradation of the polymer and form conjugate with the polymer and/or its degradation products.
  • the interaction/reaction between the basic bioactive agents and polymer carriers may occur: 1) during formulation when the basic bioactive agents are incorporated in the polymer carrier, such as microencapsulation, injection molding, extrusion molding, mixing with polymer solutions in organic solvent, and the like; 2) during storage and 3) during the process of biodegradation and the release of bioactive agents in vivo.
  • the controlled release delivery system is commonly fabricated through a step that involves dissolving/dispersing peptide agent into biodegradable polymer solution in an organic solvent
  • the stabilization of all the components in the composition at this step represents a very significant formulation challenge.
  • One common approach that has been used to overcome the challenge of manufacturing and storage stability of peptide agent and biodegradable polymer in solution or suspension is to keep the peptide agent and the polymer solution in two separate containers and mix them just before use. This assumes that the organic solvent may be separated from polymeric matrix quickly through diffusion, extraction or evaporation after the peptide agents and polymer solution are mixed.
  • An example was disclosed in U.S. Pat. Nos.
  • the solvent dissipation process can take a few hours to several days depending upon the solvents used. During this period, the presence of an organic solvent could also promote the interaction/reaction between the peptide agents and the polymer. Therefore, there is a need to develop a pharmaceutical composition that will minimize or prevent the interaction/reaction between the peptide agent and the polymer in an organic solution. There is a further need to develop a pharmaceutical composition that is stable with a satisfactory storage shelf life in a ready-to-use product configuration.
  • injectable biodegradable polymeric compositions comprising peptide agents in the form of a salt formed with a strong acid (e.g., hydrochloric acid) exhibit much higher stability than those in the form of a salt formed with a weak acid (e.g., acetic acid) or in the form of the free base.
  • a strong acid e.g., hydrochloric acid
  • Such beneficial salts of peptide agents may be formed through the neutralization of any basic groups of the peptide agents with a strong acid.
  • beneficial salts of peptide agents formed with a strong acid were formulated into injectable biodegradable polymeric compositions, the interactions/reactions between the peptide agents and the polymer are minimized or prevented.
  • beneficial salts of peptide agents formed with a strong acid allows for the preparation of a stabilized injectable composition pre-filled in a single syringe in a ready-to-use configuration with satisfactory storage stability.
  • the use of the salt of peptide agent formed with a strong acid of the present invention to enhance the stability of the injectable polymeric compositions is not contemplated by the prior art.
  • the present invention provides a stabilized injectable biodegradable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for peptide agents.
  • the present invention also provides a method of manufacturing and a method of use thereof.
  • the drug delivery system is produced easily and delivered conveniently to a subject such as a mammal or human.
  • the compositions deliver therapeutic amount of peptide agents over a desired, extended period of time, preferably from several weeks to one year.
  • the compositions are both biocompatible and biodegradable, and disappear harmlessly after delivering the dose of the peptide agents.
  • compositions in accordance with the present invention comprise a) a beneficial salt of a peptide agent formed with a strong acid that minimizes or prevents the interaction/reaction between the peptide agent and the polymer in an organic solution; b) a biodegradable polymer; c) a pharmaceutically acceptable organic solvent.
  • the pharmaceutical composition may optionally include excipients to achieve optimal delivery of the peptide agent.
  • the pharmaceutical composition may be a viscous or non-viscous liquid, gel or semisolid that moves as a fluid so that it may be injected using a syringe.
  • the pharmaceutical composition may be pre-filled into one syringe to form a product in a ready-to-use configuration.
  • the peptide agent of the present invention contains at least one basic group.
  • the peptide agent may be any peptide, oligopeptide, polypeptide, or protein that is capable of providing a biological, physiological or therapeutic effect in an animal or human.
  • the peptide agent may be any one or more of known biologically active peptide, oligopeptide, polypeptide, or protein recognized in any documents cited herein or otherwise recognized in the art.
  • the peptide agent may also stimulate or inhibit a desired biological or physiological activity within the animal or human, including without limitation, stimulate an immunogenic or immunological response.
  • the peptide agent has an N-terminus that is not a primary amine (e.g., LHRH agonists, such as leuprorelin, goserelin, LHRH antagonists, such as cetrorelix, enfuvirtide, thymosin al, abarelix, and the like).
  • the peptide agent has either an N-terminal primary amine or side chain primary amine group covalently modified with hydrophilic and/or lipophilic moieties that may be produced through pegylation, acylation, and the like.
  • both N-terminal primary amine and side chain primary amine groups of the peptide agent may also be covalently modified simultaneously with hydrophilic and/or lipophilic moieties through pegylation, acylation, and the like.
  • the strong acid may be any acid having a pKa in water less than 3, preferably less than 0, more preferably less than ⁇ 3.
  • a strong acid may be selected from, but not limited to, the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, organic sulfuric acids, alkyl sulfuric acids of 140 carbons, nitric acid, chromic acid, methanesulfonic acid, trifluromethane sulfonic acid, organic sulfonic acids, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, perchloric acid, phosphoric acid, hydrogen iodide, and the like.
  • the biodegradable polymer can be any biocompatible and pharmaceutically acceptable polymers.
  • the biodegradable polymers may be thermoplastic, which melts upon heating and solidifies upon cooling.
  • the biodegradable polymers of the invention are substantially insoluble in aqueous or body fluid, but are capable of substantially dissolving or dispersing in a water-miscible organic solvent to form a solution or suspension. Upon contact with an aqueous fluid, the water-miscible organic solvent diffuses/dissipates from the inventive composition, which causes the coagulation of the polymer to form a gel, or solid matrix encapsulating the peptide agent.
  • polymers suitable for the present composition includes, without limitation, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(maleic anhydride), and copolymers, terpolymers, or combinations or mixtures therein.
  • Lactic acid-based polymers, and copolymers of lactic acid and glycolic acid are preferably used in the present invention.
  • the PLGA polymers have a weight average molecular weights of between about 2,000 to about 100,000 and monomer ratios of lactic acid to glycolic acid of between about 50:50 to about 100:0.
  • the pharmaceutically acceptable organic solvents may be selected from a group consisting of N-methyl-2-pyrrolidone, methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, glycofurol, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, ethyl lactate, propylene carbonate, ethylene
  • one or more excipients may be incorporated in the inventive composition to achieve optimal delivery of the peptide agent.
  • Suitable excipients may include release rate modifying agents, burst effect reducing materials, buffering materials, antioxidants, and the like.
  • suitable release rate modifying agents include, but are not limited to, amphiphilic compounds or copolymers, such alkanecarboxylic acid, oleic acid, alkyl alcohol, polar lipids, surfactants, copolymers of polyethyleneglycol and polylactide or poly(lactide-co-glycolide), poloxamers, polyvinylpyrrolidone, polysorbates, and the like; esters of mono-, di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, glycerol triacetate, di(n-butyl)sebecate, and the like; polyhydroxy alcohols, such as polyethylene glycol, sorbitol, and the like; fatty acids; triesters of glycerol, such as triglycerides, medium-chain
  • suitable buffering agents include, but are not limited to, inorganic and organic salts including calcium carbonate, calcium hydroxide, calcium myristate; calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, zinc hydroxide, zinc myristate, zinc oleate, zinc palmitate, zinc stearate, zinc phosphate, and combinations thereof.
  • inorganic and organic salts including calcium carbonate, calcium hydroxide, calcium myristate; calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, zinc hydroxide, zinc myristate, zinc oleate, zinc palmitate, zinc stearate, zinc phosphate, and combinations thereof.
  • suitable antioxidants include, but are not limited to, d-alpha tocopherol acetate, ascorbyl palmitate, butylated hydroxyanidole, butylated hydroxyanisole, butylated hydroxyquinone, hydroxycomarin, butylated hydroxytoluene, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate, trihydroxybutylrophenone, vitamin E, pegylated vitamin E or vitamin E-TPGS, and the like.
  • the present invention further provides methods of making and using such compositions.
  • a method of making such compositions comprising the neutralization of basic amine groups of peptide agents to form a beneficial salt to minimize or prevent the interaction/reaction of the basic amine group with the polymer; and the combination of the beneficial salt with other components and optionally one or more excipients.
  • the beneficial salt of the peptide agent is formed first, and then combined with the polymer dissolved in an organic solvent.
  • Such compositions are physico-chemically stable prior to and during the fabrication process of a controlled delivery system such as microparticle formation or other implantable matrix formation.
  • injectable compositions are physico-chemically stable during preparation, storage, and subsequent administration to a subject and form consistent and controlled release implants upon administration to a tissue site.
  • the present invention further provides a kit for administration of the injectable composition to form a consistent and controlled release depot system
  • the kit comprises: a biodegradable polymer dissolved in a pharmaceutically acceptable solvent; a beneficial salt of a peptide agent containing at least one basic amine group formed with a strong acid dissolved or dispersed in the polymeric vehicle; and optionally one or more excipients.
  • the uniform mixture of all the components is packaged into one container.
  • the container is a syringe.
  • the present invention also provides a method comprising a step of filling a syringe with the composition to form a stable product in a ready-to-use configuration.
  • the present invention further provides a method for in-situ forming implant capable of functioning as a controlled release delivery system of the peptide agent in a subject.
  • the peptide agent is preferably incorporated into the in situ formed implant, and subsequently released into the surrounding tissue fluids and to the pertinent body tissue or organ as the polymer degrades.
  • the method comprises: administration of the injectable compositions of the present invention to an implant site by any suitable method for applying a liquid, as for example, by means of a syringe, needle, cannula, catheter, pressure applicator, and the like.
  • FIG. 1 Stability of LA in Formulations at 4° C. after 16 Months
  • FIG. 2 Molecular Weight of PLGA in Formulations at 4° C. after 16 Months
  • FIG. 3 Effect of type and concentration of PLGA on the release of leuprolide
  • FIG. 4 Effect of vitamin E on the release of LA from injectable compositions
  • FIG. 5 Effect of Miglyol 812 on the release of LA from injectable compositions
  • FIG. 6 Release profile of LA from injectable polymeric compositions following SC administration in rats
  • the present invention provides a stabilized injectable biodegradable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for peptide agents.
  • the present invention also provides a method of manufacturing and a method of use thereof.
  • compositions of the present invention comprise a) a beneficial salt of a peptide agent formed with a strong acid that minimizes or prevents the interaction/reaction between the peptide agent and the polymer in an organic solution; b) a biodegradable polymer; c) a pharmaceutically acceptable organic solvent.
  • the pharmaceutical composition may optionally include one or more excipients to achieve optimal delivery of the peptide agent.
  • the injectable polymeric composition of the present invention may be a viscous or non-viscous liquid, gel or semisolid that moves as a fluid so that it may be injected using a syringe.
  • the injectable polymeric composition may be pre-filled into one syringe to form a product kit in a ready-to-use configuration.
  • the controlled release delivery system of the present invention may be formed as an implantable polymeric matrix in vitro, or alternatively, it may be formed in-situ in the forms of a gel or a solid implant.
  • the controlled release of the peptide agent can be sustained for a desired period of time depending upon the composition of the implant. With the selections of the biodegradable polymer and other components, the duration of the sustained release of the peptide agent can be controlled over a period of time from several weeks to one year.
  • stabilized refers to a significant improvement in the stability of the components in the injectable polymeric composition, which is necessary to achieve a stable state required to develop a viable product.
  • stabilized injectable polymeric composition means that the components, e.g., the polymer and the peptide agent, of the composition retains at least 80%, preferably at least 90%, of their original molecular weight, structure and/or biological activity during manufacturing and after storage for an extended time period, e.g., months to years, preferably more than 12 months, under appropriate conditions.
  • controlled release delivery is intended to refer to the delivery of a peptide agent in vivo over a desired, extended period of time following administration, preferably from at least several weeks to one year.
  • peptide agent as used herein is in a generic sense to include poly(amino acids) that are normally generally referred to as “peptides”, “oligopeptides”, and “polypeptides” or “proteins” which are used interchangeably herein.
  • the term also includes peptide agent analogs, derivatives, acylated derivatives, glycosylated derivatives, pegylated derivatives, fusion proteins and the like.
  • the “basic peptide agent” is a peptide which is basic in nature, arising from the presence of basic amino acids, for example arginine or lysine, or arising from the N-terminus of the peptide agent, or simply a peptide agent which contains at least one basic group, optionally in the presence of one or more acidic amino acid groups.
  • the term also includes synthetic analogues of peptides, unnatural amino acids having basic functionality, or any other form of introduced basicity.
  • peptide agent is meant to include any peptide agents having diagnostic and/or therapeutic properties including, but not limited to, antimetabolic, antifungal, anti-inflammatory, antitumoral, antiinfectious, antibiotics, nutrient, agonist, and antagonist properties.
  • the peptide agents of the invention may be any peptides capable of forming a beneficial salt with a strong acid, in particular a peptide agent containing an electron donor base group such as a basic nitrogen atom, e.g. an amine, imine or ring nitrogen.
  • the peptide agents preferably contain one or more exposed protonatable amine functionalities.
  • Peptide agents useful in the preparation of the compositions of the present invention include, but are not limited to, oxytocin, vasopressin, adrenocorticotropic hormone (ACTH), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), prolactin, luteinising hormone, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones (including human, porcine, and bovine), growth hormone releasing factor, insulin, erythropoietin (including all proteins with erythropoietic activity), somatostatin, glucagon, interleukin (which includes IL-2, IL-11, IL-12, etc.), interferon-alpha, interferon-beta, interferon-gamma, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotens
  • the preferred peptide agents used herein include the peptide agents wherein the N-terminus is not a primary amine.
  • the N-terminus of the peptide agents may be a pyroglutamic acid, e.g., LHRH, and LHRH agonists such as leuprorelin, buserelin, gonadorelin, deslorelin, fertirelin, histrelin, lutrelin, goserelin, nafarelin, triptorelin, and the like.
  • the N-terminal amine group may be capped or acylated, e.g., cetrorelix, enfuvirtide, thymosin ⁇ 1, abarelix, and the like.
  • the preferred peptide agents used herein also include the peptide agents wherein the N-terminal primary amine is covalently modified with hydrophilic and/or lipophilic moieties such as through pegylation, acylation, and the like.
  • the peptide agents used herein further include the peptide agents wherein the side chain primary amine(s) are covalently modified with hydrophilic and/or lipophilic moieties such as through pegylation, acylation, and the like.
  • the preferred peptide agents used herein further include the peptide agents wherein both N-terminal primary amine and side chain primary amine groups are covalently modified simultaneously with hydrophilic and/or lipophilic moieties such as through pegylation, acylation, and the like.
  • hydrophilic moiety refers to any water-soluble linear or branched oligomer or polymer including, but not limited to, polyethylene glycol and polypropylene glycol and similar linear and branched polymers. Preferably, the molecular weight of the polymer ranges from about 500 daltons to about 50,000 daltons. Hydrophilic polymers for use in the present invention may have a reactive group incorporated for attachment to the peptide agent of interest through amine, carboxylic, hydroxyl, or thiol groups.
  • pegylation refers to the covalent conjugation of a soluble polyethylene glycol to the peptide agents.
  • Polyethylene glycol can be prepared according to standard protocols with one end capped as with a methoxy group and the other end activated for facile conjugation to active groups on peptide agents.
  • various methods for preparing polyethylene glycols and their use for pegylations are described in the art: [e.g., Roberts M J, Bentley M D, Harris J M, Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev. 2002 Jun. 17; 54(4): 459-76. Veronese F M. Peptide and protein PEGylation: a review of problems and solutions. Biomaterials. 2001 March; 22(5): 405-17 and U.S. Pat. Nos. 6,113,906; 5,446,090; 5,880,255], which are all incorporated herein by reference.
  • lipophilic moiety refers to any molecules having a solubility in water at 20° C. less than 5 mg/ml, preferably less than 0.5 mg/ml, more preferably less than 0.1 mg/mL. Such a lipophilic moiety is preferably selected from C 2-39 -alkyl, C 2-39 -alkenyl, C 2-39 -alkadienyl and steroidal residues.
  • C 2-39 -alkyl, C 2-39 -alkenyl, C 2-39 -alkadienyl are intended to cover straight chain and branched, preferably straight chain, saturated, monounsaturated and di-unsaturated hydrocarbon of 2-39 carbon atoms.
  • a lipophilic moiety covalently to a peptide agent thereof leads to a lipophilically modified peptide that may have improved therapeutic effect comparing to the native molecule.
  • This can be typically done by reacting an amine group in a peptide agent with an acid or other reactive groups in a lipophilic molecule.
  • the conjugation between peptide agent and lipophilic molecule is accomplished through an additional moiety such as a bridge, spacer, or linkage moiety, which can be degradable or non-degradable.
  • strong acid is meant to include any acids with a pKa less than 3, preferably less than 0, and more preferably less than ⁇ 3.
  • the strong acids suitable for the present invention may be selected from, but not limited to, the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, chromic acid, sulfuric acid, methanesulfonic acid, trifluromethane sulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, pamoic acid, perchloric acid, phosphoric acid, hydrogen iodide, and the like.
  • the “strong acid” of the present invention also includes any organic sulfuric acids such as alkyl, aryl or alkylaryl sulfuric acids of 140 carbons, preferably less than 18 carbons, and more preferably less than 6 carbons, and organic sulfonic acids such as alkane, arylalkane, arene, or alkene sulfonic acids of 1-40 carbons, preferably less than 18 carbons, and more preferably less than 6 carbons.
  • organic sulfuric acids such as alkyl, aryl or alkylaryl sulfuric acids of 140 carbons, preferably less than 18 carbons, and more preferably less than 6 carbons
  • organic sulfonic acids such as alkane, arylalkane, arene, or alkene sulfonic acids of 1-40 carbons, preferably less than 18 carbons, and more preferably less than 6 carbons.
  • a beneficial salt of a peptide agent is meant to include any salts of a peptide agent formed with a strong acid.
  • the beneficial salts of peptide agents can be prepared by simple acid and base titration or neutralization.
  • the beneficial salts of peptide agents can be prepared during its synthesis and purification processes. Alternatively, they can be prepared from peptide agent in the form of a free base. The free base is dissolved in a suitable liquid medium. This solution of the peptide agent is mixed with a solution of a strong acid to form the beneficial salts by removing the solvent through suitable means such as filtration or lyophilization.
  • the peptide agent is in its common commercially available form of a salt formed with a weak acid (i.e., pKa>3)
  • the weak acid can be replaced by a strong acid through common ion-exchange methods such as lyophilization, precipitation or other methods known in the art.
  • leuprolide acetate is dissolved in a suitable liquid medium, e.g., water.
  • This solution of the peptide agent is mixed with an aqueous solution of a strong acid such as hydrochloric acid.
  • the peptide agent When the peptide acetate and a strong acid such as hydrochloric acid are dissolved in water, the peptide tends to be associated with chloride ion, as the stronger acid HCl displaces the weaker carboxylic acetic acid.
  • the solvent and liberated acetic acid (or other weak but volatile carboxylic acid) may be removed under vacuum.
  • the mixture solution is freeze-dried to remove water and weaker acid to form the beneficial salts. If the peptide agent is not stable under low pH, the beneficial salts of the peptide agent can be prepared through extensive dialysis against very low concentration of a strong acid.
  • the injectable polymeric compositions of the present invention may contain peptide agent in a range of 0.01 to 40% by weight.
  • the optimal drug loading depends upon the period of release desired and the potency of the peptide agent. Obviously, for peptide agent of low potency and longer period of release, higher levels of incorporation may be required.
  • biodegradable refers to a material that gradually decomposes, dissolves, hydrolyzes and/or erodes in situ.
  • biodegradable polymers are polymers that are hydrolyzable, and/or bioerode in situ primarily through hydrolysis and/or enzymolysis.
  • biodegradable polymer as used herein is meant to include any biocompatible and/or biodegradable synthetic and natural polymers that can be used in vivo, provided the polymer is at least substantially insoluble in aqueous medium or body fluid.
  • substantially insoluble refers that the insolubility of the polymer must be sufficient to result in precipitation of the polymer in aqueous medium or body fluid.
  • the solubility of the polymers is less than 1% by weight, and more preferably less than 0.1%.
  • Suitable biodegradable polymers are disclosed, e.g., in U.S. Pat. Nos. 4,938,763; 5,278,201; 5,278,2012; 5,324,519; 5,702,716; 5,744,153; 5,990,194; and 6,773,714.
  • polymers are polylactides, polyglycolides, polycaprolactones, polydioxanones, polycarbonates, polyhydroxybutyrates, polyalkylene oxalates, polyanhydrides, polyesteramides, polyurethanes, polyacetals, polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates, poly(malic acid), and polyorthoesters, and copolymers, block copolymers, branched copolymers, terpolymers and combinations and mixtures thereof.
  • the block copolymers include A-B-A block copolymers, B-A-B block copolymers, and/or A-B block copolymers and/or branched copolymers.
  • the preferred block copolymers are those wherein the A block comprises a hydrophobic polymer and the B block comprises a hydrophilic polymer.
  • the most preferred polymeric matrices are defined where the A block is a biodegradable polymer selected from the group consisting of polylactides, polyglycolides, poly(lactide-co-glycolide)s, polyanhydrides, poly(ortho ester)s, polyetheresters, polycaprolactones, polyesteramides, poly( ⁇ -caprolactone)s, poly(hydroxybutyric acid)s, and blends and copolymers thereof, and the B block is polyethylene glycol or monofunctionally derivatized polyethylene glycol such as methoxy polyethylene glycol. Many of these combinations may form acceptable thermal reversible gels.
  • the A block is a biodegradable polymer selected from the group consisting of polylactides, polyglycolides, poly(lactide-co-glycolide)s, polyanhydrides, poly(ortho ester)s, polyetheresters, polycaprolactones, polyesteramides, poly( ⁇ -caprolactone)s,
  • Suitable molecular weights for polymers may be determined by a person of ordinary skill in the art. Factors that may be considered when determining molecular weights include desired polymer degradation rate, mechanical strength, and rate of dissolution of polymer in organic solvents. Typically, a suitable range of weight averaged molecular weights of polymers is of about 2,000 Daltons to about 100,000 Daltons with a polydispersity of from 1.1 to 2.5, depending upon which polymer is selected for use, among other factors.
  • the injectable polymeric compositions of the present invention may contain biodegradable polymer in a range of 10% to 70% by weight.
  • the viscosity of the injectable compositions of the invention depends on the molecular weight of the polymer and organic solvent used. Typically, when the same solvent is used, the higher the molecular weight and the concentration of the polymer, the higher the viscosity.
  • concentration of the polymer in the compositions is less than 70% by weight. More preferably concentration of the polymer in the compositions is between 30 to 60% by weight.
  • Poly(lactic acid), and copolymers of lactic acid and glycolic acid are preferably used in the present invention.
  • the polymers or thermoplastic polyesters
  • the polymers have monomer ratios of lactic acid to glycolic acid of between about 50:50 to about 100:0 and weight average molecular weights of between about 2,000 to about 100,000.
  • the biodegradable thermoplastic polyesters can be prepared using the methods known in the art, e.g., polycondensation and ring-opening polymerization (e.g., U.S. Pat. Nos.
  • the terminal groups of the poly(DL-lactide-co-glycolide) can either be hydroxyl, carboxylic, or ester depending upon the method of polymerization.
  • the suitable polymers may include a monofunctional alcohol or a polyol residue and may not have a carboxylic acid terminus. Examples of monofunctional alcohols are methanol, ethanol, or 1-dodecanol.
  • the polyol may be a diol, triol, tetraol, pentaol and hexaol including ethylene glycol, 1,6-hexanediol, polyethylene glycol, glycerol, saccharides, reduced saccharides such as sorbitol, and the like.
  • PLGAs are available commercially, and the PLGAs of specific compositions can be readily prepared according to the prior art.
  • the PLGAs of various monomer ratios and molecular weights are available from Boehringer-Ingelheim (Petersburg, Va., USA), Lakeshore Biomaterials (Birmingham, Ala., USA), DURECT Corporation (Pelham, Ala.).
  • the type, molecular weight, and amount of biodegradable polymer present in the compositions can influence the length of time in which the peptide agent is released from the controlled release implant.
  • the selection of the type, molecular weight, and amount of biodegradable polymer present in the compositions to achieve desired properties of the controlled release implant can be determined by simple experimentations.
  • the liquid composition can be used to formulate a controlled release delivery system for leuprolide hydrochloride.
  • the biodegradable thermoplastic polyester can preferably be 85/15 poly (DL-lactide-co-glycolide) containing a hydroxyl terminal group and a lauryl ester terminus; can be present in about 30% to about 60% of the composition by weight; and can have an average molecular weight of about 15,000 to about 50,000.
  • the liquid composition can be used to formulate a controlled release delivery system for leuprolide hydrochloride.
  • the biodegradable thermoplastic polyester can preferably be 85/15 poly (DL-lactide-co-glycolide) containing two hydroxyl terminal groups; can be present in about 30% to about 60% of the composition by weight; and can have an average molecular weight of about 15,000 to about 50,000.
  • the liquid composition can be used to formulate a controlled release delivery system for leuprolide hydrochloride.
  • the biodegradable thermoplastic polyester can preferably be 85/15 poly (DL-lactide-co-glycolide) containing a carboxylic acid terminal groups; can be present in about 30% to about 60% of the composition by weight; and can have an average molecular weight of about 15,000 to about 50,000.
  • the composition can be used to formulate a controlled release delivery system of leuprolide.
  • the biodegradable polymer can preferably be 100/0 poly (DL-lactide) with/without carboxylic acid terminal groups; can be present in about 40% to about 60% of the composition by weight; and can have an average molecular weight of about 8,000 to about 50,000.
  • the term “pharmaceutically acceptable organic solvent” is meant to include any biocompatible organic solvents that are miscible or dispersible in aqueous or body fluid.
  • the term “dispersible” means that the solvent partially soluble or miscible in water.
  • a single solvent or a mixture of solvents has a solubility or miscibility in water of greater than 0.1% by weight. More preferably, the solvent has a solubility or miscibility in water of greater than 3% by weight. Most preferably, the solvent has a solubility or miscibility in water of greater than 7% by weight.
  • the suitable organic solvent should be able to diffuse into body fluid so that the liquid composition coagulates or solidifies. Single and/or mixture of such solvents can be employed; the suitability of such solvents can be determined readily by simple experimentations.
  • Examples of pharmaceutically acceptable organic solvent include, but not limited to, N-methyl-2-pyrrolidone, methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, glycofurol, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, ethyl lactate, propylene carbonate, ethylene carbonate,
  • the solubility of the biodegradable polymers in various pharmaceutically acceptable organic solvents will differ depending upon the characteristics of the polymers and their compatibility with various solvents. Thus, the same polymer will not be soluble to the same extent in different solvents.
  • PLGA has a much higher solubility in N-methyl-2-pyrrolidone (NMP) than that in triacetin.
  • NMP N-methyl-2-pyrrolidone
  • NMP N-methyl-2-pyrrolidone
  • the injectable polymeric compositions of the present invention typically contain an organic solvent in a range of 30% to 80% by weight.
  • the viscosity of the injectable compositions of the invention depends on the molecular weight of the polymer and organic solvent used.
  • concentration of the polymer in the compositions is less than 70% by weight. More preferably concentration of the polymer in solutions is between 30 to 60% by weight.
  • excipients as used herein is meant to include any useful ingredient in the composition aside from the peptide agent or the biodegradable polymers used to form the composition. Suitable excipients include release rate modifying agents, burst effect reducing materials, buffering materials, antioxidants, and the like.
  • suitable release rate modifying agents include, but not limited to, amphiphilic compounds or copolymers, such alkanecarboxylic acid, oleic acid, alkyl alcohol, polar lipids, surfactants, copolymers of polyethyleneglycol and polylactide or poly(lactide-co-glycolide), poloxamers, polyvinylpyrrolidone, polysorbates, and the like; esters of mono-, di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, glycerol triacetate, di(n-butyl)sebecate, and the like; polyhydroxy alcohols, such as polyethylene glycol, sorbitol, and the like; fatty acids; triesters of glycerol, such as triglycerides, medium-chain t
  • the release rate modifying agents may be present in the injectable polymeric composition in an amount effective to reduce the initial burst of peptide agent released from the polymeric composition during the first 24 hours after implantation.
  • the polymeric composition includes about 1% to about 50% by weight, more preferably about 2% to about 20% by weight of the release rate modifying agents.
  • suitable buffering agents include, but are not limited to, inorganic and organic salts including calcium carbonate, calcium hydroxide, calcium myristate; calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, zinc hydroxide, zinc myristate, zinc oleate, zinc palmitate, zinc stearate, zinc phosphate, and combinations thereof.
  • inorganic and organic salts including calcium carbonate, calcium hydroxide, calcium myristate; calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, zinc hydroxide, zinc myristate, zinc oleate, zinc palmitate, zinc stearate, zinc phosphate, and combinations thereof.
  • the buffering agents may be present in the injectable polymeric composition in an amount effective to stabilize the pH within the implants during the degradation process.
  • the polymeric composition includes about 1 wt % to about 30 wt %, more preferably about 2 wt % to about 15 wt % of the buffering agents.
  • suitable antioxidants include, but are not limited to, d-alpha tocopherol acetate, ascorbyl palmitate, butylated hydroxyanidole, butylated hydroxyanisole, butylatedhydroxyquinone, hydroxycomarin, butylated hydroxytoluene, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate, trihydroxybutylrophenone, vitamin E, pegylated vitamin E or vitamin E-TPGS, and the like.
  • the antioxidants may be present in the injectable polymeric composition in an amount effective to scavenge any radicals or peroxides generated within the implants.
  • the polymeric composition includes about 1 wt % to about 30 wt %, more preferably about 3 wt % to about 15 wt % of the antioxidants.
  • the injectable composition is packaged into a kit comprising a step to fill the composition into a syringe in a ready-to-use configuration.
  • composition in the kit is stable for a reasonable period of time, preferably at least one year, to have a suitable storage shelf-life under controlled storage conditions.
  • the composition is preferably injected into a subject to form in situ an implant, from which the peptide agent is released in a therapeutic effective amount over a desired, extended period of time.
  • the stabilized injectable biodegradable polymeric composition of the present invention can be prepared by appropriately combining a beneficial salt of a peptide agent, a biodegradable polymer, a pharmaceutically acceptable organic solvent, and an optional excipient.
  • the composition for administration may conveniently presented in dosage unit form and may be prepared by any of the methods known in the art of pharmacy.
  • One preferred method of preparing the composition of the present invention is to dissolve a biodegradable polymer and/or an excipient in a pharmaceutically acceptable organic solvent to obtain a uniform polymer solution/suspension first. Then the beneficial salt of a peptide agent is added to this solution/suspension. The components are thoroughly mixed using any proper means to obtain a uniform solution or suspension. Then an appropriate amount of the solution or suspension is transferred into a syringe to obtain a ready-to-use product.
  • the level of incorporation of the beneficial salt and polymer in the composition of the invention will naturally vary, depending upon the potency of the peptide agent component, the period of time over which delivery of the agent is desired, the solubility of the polymer in the solvent, and the volume and viscosity of the injectable composition which is desired to administer.
  • the injectable biodegradable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for peptide agents contains about 0.01% to 40% of the beneficial salt of a peptide agent and about 10% to 70% of a poly(lactide-co-glycolide) polymer.
  • the composition further contains about 30% to 70% of a pharmaceutically acceptable organic solvent.
  • the composition further contains about 1% to 40% of a suitable excipient including release rate modifying agents, burst effect reducing materials, buffering materials, antioxidants, tissue transporting agents and the like as defined above.
  • the injectable composition is transferred into a sterile container suitable for injection administration, e.g., a syringe.
  • a sterile container suitable for injection administration e.g., a syringe.
  • the container is packaged for storage and the components of the composition retains at least 80%, preferably 90%, of their original molecular weight, structure and/or biological activity during manufacturing and storage processes or prior to administration to a subject such as an animal or human.
  • the stabilized compositions can be administered to a subject where controlled release delivery of a peptide agent is desired.
  • subject is intended to include warm-blooded animals, preferably mammals, most preferably humans.
  • the term “administered to a subject” is intended to refer to dispensing, delivering or applying a composition (e.g., pharmaceutical formulation) to a subject by any suitable route for delivery of the composition to the desired location in the subject.
  • a composition e.g., pharmaceutical formulation
  • the composition of the present invention can be administered by injection and/or implantation subcutaneously, intramuscularly, intraperitoneally, or intradermally to provide the desired dosage based on the known parameters for treatment of the various medical conditions with the peptide agent.
  • controlled release delivery is intended to refer to continual delivery of a peptide agent in vivo over a period of time following administration, preferably from at least several weeks to one year.
  • Sustained controlled release delivery of the agent can be demonstrated by, for example, the continued therapeutic effect of the agent over time (e.g., for an LHRH analogue, sustained delivery of the analogue can be demonstrated by continued suppression of testosterone synthesis over time).
  • sustained delivery of the peptide agent may be demonstrated by detecting the presence of the agent in vivo over time.
  • the amount of the injectable composition administered will typically depend upon the desired properties of the controlled release implant.
  • the amount of the injectable composition can influence the length of time in which the peptide agent is released from the controlled release implant.
  • the volume of the injectable polymeric composition of the present invention to be injected to a subject ranges from 0.1 mL to 2.0 mL; preferably from 0.2 mL to 1.0 mL; and more preferably from 0.3 mL to 0.5 mL.
  • the present invention further provides a method for in situ forming an implant in a subject comprising administering to a subject an effective amount of the injectable composition comprising: a) a beneficial salt of a peptide agent formed with a strong acid which minimizes or prevents the interaction/reaction between the peptide agent and the polymer in an organic solution; b) a biodegradable polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more excipients to achieve optimal delivery of the peptide agent; and allowing the solvent to dissipate into the surrounding aqueous environment to transform the liquid composition into a depot by phase separation.
  • the depot may be a viscous gel, a semi-solid, or a solid matrix.
  • the depot may also be porous or non-porous.
  • the depot serves as the delivery system from which the peptide agent is released over a desired and extended period of time.
  • the injectable composition of the present invention may be administered to fit into a body cavity to form a depot system.
  • Such cavities include the cavities created after a surgery or natural body cavity such as vagina, anus, and the like.
  • the liquid biodegradable polymeric composition may be fabricated into implantable polymeric matrices. Wherein the liquid biodegradable polymeric composition retains at least 90%, preferably 95%, of their original molecular weight, structure and/or biological activity before and during the fabrication process.
  • the term of “implantable polymeric matrices” is intended to include particles, films, pellets, cylinders, discs, microcapsules, microspheres, nanospheres, microparticles, wafers, and other known polymeric configurations used for drug delivery.
  • the implantable polymeric matrices in the form of microspheres are produced by encapsulating the beneficial salt of peptide agents into the polymer.
  • the beneficial salt of peptide agents can be encapsulated using various biocompatible and/or biodegradable polymers having unique properties that are suitable for delivery to different biological environments or for effecting specific functions.
  • the rate of dissolution and, therefore, delivery of peptide agent is determined by the particular encapsulation technique, polymer composition, polymer crosslinking, polymer thickness, polymer solubility, size and solubility of biologically active compound/polyanion complex.
  • the beneficial salts of peptide agents to be encapsulated are dissolved or suspended in a polymer solution in an organic solvent.
  • the polymer solution must be concentrated enough to completely coat the beneficial salt after they are added to the solution.
  • Such an amount is one that provides a weight ratio of the beneficial salt of peptide agents to polymer between about 0.01 and about 50, preferably between about 0.1 and about 30.
  • the beneficial salt of peptide agents should be kept suspended and not allowed to aggregate as they are coated by contact with the polymer.
  • a polymer solution of the beneficial salts of peptide agents can therefore be subjected to a variety of microencapsulation techniques including spray drying, spray congealing, emulsion, and solvent evaporation emulsion.
  • the beneficial salt of peptide agents is dissolved or suspended in a polymer solution in an organic solvent.
  • the solution or suspension is transferred to a larger volume of an aqueous solution containing an emulsifier.
  • the organic phase is emulsified, where the organic solvent evaporates or diffuses away from the polymer.
  • the solidified polymer encapsulates the beneficial salt of peptide agents to form a polymer matrix.
  • the emulsifier helps to reduce the interfacial surface tension between the various phases of matter in the system during the hardening phase of the process. Alternatively, if the encapsulating polymer has some inherent surface activity, there may be no need for addition of a separate surface-active agent.
  • Emulsifiers useful to prepare encapsulated the beneficial salt of peptide agents according to the present invention include poloxamers and polyvinyl alcohol as exemplified herein, surfactants and other surface active compounds which can reduce the surface tension between the polymer encapsulated beneficial salt of peptide agents and the solution.
  • Organic solvents useful to prepare the microspheres of the present invention also include acetic acid, acetone, methylene chloride, ethyl acetate, chloroform and other non-toxic solvents that will depend on the properties of the polymer. Solvents should be chosen to dissolve the polymer and are ultimately non-toxic.
  • these implantable polymeric matrices can be administered to a subject where sustained controlled release delivery of a peptide agent is desired.
  • the implantable polymeric matrices of the invention can be administered by injection and/or implantation subcutaneously, intramuscularly, intraperitoneally, or intradermally to provide the desired dosage based on the known parameters for treatment of the various medical conditions with the peptide agent.
  • Peptide agent or peptide derivative containing at least one basic functional group is dissolved in water. Stoichiometric amounts of a strong acid are added to the aqueous solution of the peptide agent, resulting in neutralization of the basic groups in the peptide agent.
  • the salt is obtained by precipitation, filtration and/or lyophilization.
  • Leuprolide is a luteinizing hormone releasing hormone (LHRH) agonist containing 9 amino acid residues and two basic functionalities (a histidine and an arginine group). Its N-terminal amine was blocked in the form of pyroglutamic acid. It has been used in the treatment of prostate cancer and endometriosis.
  • LHRH leuprolide acetate
  • LA-Ac Leuprolide acetate
  • LA-HCl Leuprolide Hydrochloride
  • leuprolide acetate (PPL Lot#PPL-LEUP0401A) was dissolved in 20 mL water. 32 ⁇ L of methanesulfonic acid was added and mixed well (molar ratio of leuprolide acetate to methanesulfonic acid ⁇ 1:2). The solution was freeze-dried for 72 h to remove acetic acid. The dried powder was re-dissolved in water and freeze-dried again.
  • Palmitoyl-Octreotide PAL-OCT
  • octreotide acetate 50 mg was dissolved in 1000 uL of anhydrous DMSO containing 100 uL TEA. 17.1 mg of Palmitic acid N-hydroxysuccinimide ester (Mw 353.50) was dissolved in 3 mL anhydrous DMSO and added by direct injection to the peptide solution. The reaction was allowed to proceed for overnight at room temperature. The mixture was poured into diethyl ether to precipitate palmitoylated octreotide. The precipitate was washed with diethyl ether twice and then dried under vacuum. The resulting acylated peptide was in a form of white powder. The beneficial salt of the acylated peptide was formed by neutralizing the residual basic amine groups using a strong acid.
  • the mobile phase was run with a linear gradient from 30 to 60% eluent B for 20 min at a flow rate of 1 ml/min and the UV absorbance of the elution was monitored at 215 nm.
  • the elution fractions corresponding to respective peaks were collected separately, purged with nitrogen, and lyophilized.
  • site-specific PEGylation of octreotide can be obtained.
  • a solution of octreotide acetate (10 mg/mL) in 20 mM sodium cyanoborohydride (NaCNBH 3 ) and 0.1 M acetate buffer at pH 5 was added to a vial containing 3 molar equivalent amount of monomethoxy PEG-propionaldehyde (ALD-mPEG, MW 2000 dalton) in water.
  • ALD-mPEG monomethoxy PEG-propionaldehyde
  • the reaction was allowed to proceed with stirring at 4° C. overnight.
  • the reaction mixture was separated by using reversed-phase HPLC (RP-HPLC) on C-18 (YMC ODS-A 5 ⁇ m, 4.6 ⁇ 250 mm, Waters Corporation).
  • the mobile phase consisted of 0.1% TFA in water (A) and CAN containing 0.1% TFA (B).
  • the mobile phase was run with a linear gradient from 30 to 60% eluent B for 20 min at a flow rate of 1 ml/min and the UV absorbance of the elution was monitored at 215 nm.
  • the elution fractions corresponding to respective peaks were collected separately, purged with nitrogen, and lyophilized.
  • the beneficial salt of the pegylated peptide is formed by neutralizing the residual basic amine groups using a strong acid.
  • Poly(DL-lactide-co-glycolide) (PLGA) of an 85/15 ratio of lactide to glycolide (DLPLG85/15, IV: 0.28) with a lauryl ester end group was dissolved in N-methyl-2-pyrrolidone (NMP) to give a 50% solution by weight.
  • NMP N-methyl-2-pyrrolidone
  • the leuprolide salts were mixed with the PLGA solution in NMP to give a uniform injectable composition at ratios shown in the Table 1.
  • the injectable compositions were filled into 1.2 mL polypropylene syringes with luer-lock tips. Then the pre-filled syringes were sealed using luer-lock caps.
  • the capped syringes were packaged in a container and sealed in a plastic bag under vacuum and then stored at 4° C. and room temperature ( ⁇ 22° C.) for up to 18 months.
  • the injectable composition was sampled at 24 h, 1, 2, 3, 6, 12, and 18 month time points. Purity of leuprolide in the sample was determined by HPLC. Molecular weight of the polymer was determined by gel permeation chromatography (GPC) using polystyrene standards with known molecular weights.
  • LA-AC LA-HCl-1 LA-MS 0 100.0 100.0 100.0 1 89.3 100.0 100.0 3 100.0 100.0 100.0 6 94.1 100.0 100.0 12 88.2 100.0 98.9 18 76.9 98.5 98.3
  • Table 4 and 5 showed the changes of molecular weight of the polymer in different formulations. Comparing to blank control, the molecular weight of PLGA in leuprolide acetate formulation decreased more than 10% at 4° C. and more than 90% at room temperature after 6 months. The molecular weight of PLGA in leuprolide hydrochloride and leuprolide mesylate formulations was the same as that of the blank control at both 4° C. and RT even after 12 months. However, after 12 months, more than 90% of the polymer from both blank control and leuprolide hydrochloride and leuprolide mesylate formulations was degraded.
  • Poly(DL-lactide-co-glycolide) (PLGA) of an 85/15 ratio of lactide to glycolide (DLPLG85/15, IV: 0.28) with a lauryl ester end group was dissolved in dimethylsulfoxide (DMSO) to give a 50% solution by weight.
  • DMSO dimethylsulfoxide
  • the leuprolide salts were mixed with the PLGA solution in DMSO to give a uniform injectable composition at ratios shown in the Table 6.
  • the injectable compositions were filled into 1.2 mL polypropylene syringes with luer-lock tips. Then the pre-filled syringes were sealed using luer-lock caps.
  • the capped syringes were packaged in a container and sealed in a plastic bag under vacuum and then stored at 4° C. and room temperature ( ⁇ 22° C.) for up to 16 months.
  • the injectable composition was sampled at pre-defined time points. Purity of leuprolide in the sample was determined by HPLC. Molecular weight of the polymer was determined by gel permeation chromatography (GPC) using polystyrene standards with known molecular weights.
  • FIGS. 1 and 2 showed the degradation of leuprolide in PLGA in solutions in DMSO at 4° C. over time. Up to about 20% of leuprolide was degraded in the case of leuprolide acetate, while less than 5% of leuprolide was degraded for leuprolide hydrochloride and leuprolide mesylate formulations after 16 months.
  • FIG. 5 showed the changes of molecular weight of PLGA in different formulations.
  • the molecular weight of PLGA in leuprolide acetate formulation decreased about 40% at 4° C. after 16 months.
  • the molecular weight of PLGA in injectable polymeric compositions containing leuprolide hydrochloride and leuprolide mesylate was comparable to that of the control at 4° C. after 16 months.
  • the results indicate that the salts of leuprolide formed with strong acid such as HCl and methanesulfonic acid almost completely prevent the interaction/reaction between the peptide and PLGA in DMSO solution. While the weak acid such as acetic acid does not prevent the deleterious interaction/reaction between the peptide and PLGA in DMSO solution.
  • FIG. 3 shows the cumulative release of leuprolide for different formulations over time.
  • the polymer vehicle solutions with and without excipients were prepared as following: PLA 100DLPL (0.26 IV, Lakeshore, Ala.) with a lauryl ester end group and Vitamin E TPGS were dissolved in NMP at suitable amount according to the Table 7. Then suitable amount of leuprolide hydrochloride (LAHCl) was mixed with the polymer solutions at 15% by weight. The formulations were thoroughly mixed to obtain uniform formulations. TABLE 7 Effect of excipients on the in vitro release of leuprolide PLA 100DLPL NMP Vitamin E TPGS LAHCl Sample (%) (%) (%) (%) (%) Formulation-1 47 38 0 15 Formulation-2 44.5 36.4 4.2 15
  • FIG. 4 shows the cumulative release of leuprolide for different formulations over time.
  • Vitamin E TPGS may be useful for extending the delivery of the peptide and also functioning as an antioxidant.
  • the polymer vehicle solutions with and without excipients were prepared as following: PLA 100D040 (0.34 IV, Durect, Calif.) with a lauryl ester end group and medium chain triglyceride Miglyol 812 were dissolved in NMP at suitable amount according to the Table 8. Then suitable amount of leuprolide hydrochloride (LAHCl) was mixed with the polymer solutions at 15% by weight. The formulations were thoroughly mixed to obtain uniform formulations. TABLE 8 Effect of excipients on the in vitro release of leuprolide PLA 100D040 NMP Miglyol 812 LAHCl Sample (%) (%) (%) (%) (%) (%) Formulation-1 42.5 42.5 0 15 Formulation-2 42.5 38.3 4.2 15
  • FIG. 5 shows the cumulative release of leuprolide for different formulations over time.
  • Miglyol 812 did significantly reduced the initial burst release of leuprolide, and seem to maintain the release rate of leuprolide at later stages. Thus, Miglyol 812 may be useful for extending the delivery of the peptide. Comparing to the results in Example 11, it seems the molecular weight of the polymer also significantly affect the initial burst release of leuprolide. It seems that the smaller molecular weight of the PLA, the smaller the initial burst release rate of leuprolide.
  • Poly(DL-lactide-co-glycolide) of an 85/15 ratio of lactide to glycolide (DLPLG85/15, IV: 0.28) containing a lauryl ester end group was dissolved in N-methyl-2-pyrrolidone (NMP) to give a 55% solution by weight.
  • NMP N-methyl-2-pyrrolidone
  • the leuprolide salt, i.e., Leuprolide mesylate or Leuprolide HCl were mixed with the PLGA solution in NMP to give a uniform injectable formulation at a drug loading of about 12%.
  • the injectable formulations were transferred into 1.2 ml polypropylene syringes with luer-lock tips and a 19 gauge thin-wall needle attached.
  • Each formulation was then injected into the rats subcutaneously at a volume of about 100 ⁇ L with 6 animals per group.
  • the serum samples were collected from each animal at 3 hour, 1, 3, 7, 14, 28, 42, 56, and 70 days post injection.
  • the serum samples were analyzed for leuprolide concentration by ELISA using the kits available from Peninsula Laboratories Inc.
  • the leuprolide remaining in the implants at various times was analyzed by HPLC.
  • FIG. 6 shows the release profile of leuprolide from two different formulations up to 70 days. Both formulations showed initial burst release of leuprolide. The formulation containing LAHCl reached C max of 661.6 ng/mL at 3 hours, and the formulation containing LAMS reached C max of 370.6 ng/mL also at 3 hours. Both formulations showed sustained release of leuprolide over an extended time period. The formulation containing LAMS showed a more constant serum levels of leuprolide than that obtained from the formulation containing LAHCl.
  • Poly(DL-lactide-co-glycolide) of a 85/15 ratio of lactide to glycolide (DLPLG85/15, IV: 0.27) containing a 1,6-hexanediol moiety is dissolved in N-methyl-2-pyrrolidone (NMP) to give a 50% solution by weight.
  • NMP N-methyl-2-pyrrolidone
  • the leuprolide salt, i.e., Leuprolide acetate or Leuprolide HCl are mixed with the PLGA solution in NMP to give a uniform injectable formulation at a drug loading of about 12%.
  • the injectable formulations are transferred into 1.2 ml polypropylene syringes with luer-lock tips and a 19 gauge thin-wall needle attached.
  • Each formulation is then injected into the rats subcutaneously at a volume of about 100 ⁇ L with 6 animals per group.
  • the serum samples are collected from each animal at 3 hour, 1, 3, 7, 14, 28, 42, 56, 70, 91, 112, 133, 154, 175, and 206 days post injection.
  • the serum samples are analyzed for leuprolide concentration by ELISA using the kits available from Peninsula Laboratories Inc., and for testosterone concentration by LC/MS/MS.
  • the leuprolide remaining in the implants at various times may be analyzed by HPLC.
  • LHRH analogues such as buserelin, deslorelin, fertirelin, histrelin, lutrelin, goserelin, nafarelin, triptorelin, cetrorelix, abarelix, and other peptides, such as GLP-1, PYY, etc, and other polymers and solvents.
  • a biodegradable polymeric composition may be injected subcutaneously or intramuscularly to form an implant in situ, applied as a transdermal cream, and also introduced to the patient as a rectal or vaginal suppository.
  • Poly(lactide-co-glycolide (PLGA) microspheres are prepared by an oil-in-water (O/W) single emulsion technique.
  • PLGA is dissolved in methylene chloride (DCM).
  • DCM methylene chloride
  • the drug is mixed with the PLGA solution in DCM.
  • the mixed solution or suspension is emulsified in 500 mL of 0.5-1% (w/v) PVA (PVA, 88% hydrolyzed, average molecular weight of 31,000-50,000, Sigma-Aldrich) solution pre-cooled in the refrigerator at 4° C.
  • the emulsion is stirred continuously for 3 h at RT to evaporate the DCM.
  • the hardened microspheres are collected, washed three times with deionized water, and then freeze-dried.
  • the biodegradable polymer consisting of a poly-(lactic acid-co-glycolic acid) having a ratio of lactide to glycolide of 50:50 to 100:0 such as RG503H (Boehringer Ingelheim Chemicals, Inc. USA) is dissolved in a volatile organic solvent, such as ethyl acetate or methylene chloride.
  • a beneficial salt as defined herein such as goserelin mesylate (0.01%-30% by weight relative to the polymer) is dissolved/dispersed in the polymer solution.
  • the solution is thoroughly mixed to obtain a uniform solution or suspension.
  • the solvent is removed by evaporation. This is done by a spray drying procedure to form small uniform particles for injection. This can be done also in a mold to form an implant.
  • the resulting polymer matrices can also be ground to a powder and formulated as an injectable suspension.
  • solid dosage forms can be injected subcutaneously or intramuscularly, or can be placed surgically under the skin in the form of an implant, or given orally as part of an oral delivery system for peptide agents.
  • the solid microparticles may also be prepared as a suspension or a non-aqueous solution, which may also be administered to a patient via inhalation, for pulmonary drug delivery.
  • the microparticles may also be suspended in oil and introduced to the patient as a rectal or vaginal suppository.
US11/653,636 2006-01-18 2007-01-16 Pharmaceutical compositions with enhanced stability Abandoned US20070196416A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US11/653,636 US20070196416A1 (en) 2006-01-18 2007-01-16 Pharmaceutical compositions with enhanced stability
TW96110525A TWI376241B (en) 2007-01-16 2007-03-27 Pharmaceutical compositions with enhanced stability
US15/230,413 US9572857B2 (en) 2006-01-18 2016-08-06 Pharmaceutical compositions with enhanced stability
US15/406,321 US9744207B2 (en) 2006-01-18 2017-01-13 Pharmaceutical compositions with enhanced stability
US15/661,066 US10251956B2 (en) 2006-01-18 2017-07-27 Methods of making pharmaceutical compositions with enhanced stability
US16/376,028 US10646572B2 (en) 2006-01-18 2019-04-05 Pharmaceutical compositions with enhanced stability

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75989106P 2006-01-18 2006-01-18
US11/653,636 US20070196416A1 (en) 2006-01-18 2007-01-16 Pharmaceutical compositions with enhanced stability

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/230,413 Continuation US9572857B2 (en) 2006-01-18 2016-08-06 Pharmaceutical compositions with enhanced stability

Publications (1)

Publication Number Publication Date
US20070196416A1 true US20070196416A1 (en) 2007-08-23

Family

ID=38288166

Family Applications (5)

Application Number Title Priority Date Filing Date
US11/653,636 Abandoned US20070196416A1 (en) 2006-01-18 2007-01-16 Pharmaceutical compositions with enhanced stability
US15/230,413 Active US9572857B2 (en) 2006-01-18 2016-08-06 Pharmaceutical compositions with enhanced stability
US15/406,321 Active US9744207B2 (en) 2006-01-18 2017-01-13 Pharmaceutical compositions with enhanced stability
US15/661,066 Active US10251956B2 (en) 2006-01-18 2017-07-27 Methods of making pharmaceutical compositions with enhanced stability
US16/376,028 Active US10646572B2 (en) 2006-01-18 2019-04-05 Pharmaceutical compositions with enhanced stability

Family Applications After (4)

Application Number Title Priority Date Filing Date
US15/230,413 Active US9572857B2 (en) 2006-01-18 2016-08-06 Pharmaceutical compositions with enhanced stability
US15/406,321 Active US9744207B2 (en) 2006-01-18 2017-01-13 Pharmaceutical compositions with enhanced stability
US15/661,066 Active US10251956B2 (en) 2006-01-18 2017-07-27 Methods of making pharmaceutical compositions with enhanced stability
US16/376,028 Active US10646572B2 (en) 2006-01-18 2019-04-05 Pharmaceutical compositions with enhanced stability

Country Status (14)

Country Link
US (5) US20070196416A1 (es)
EP (1) EP1984009B1 (es)
JP (1) JP5242415B2 (es)
KR (2) KR20150017777A (es)
CN (1) CN101400363B (es)
AU (1) AU2007207618B2 (es)
CA (1) CA2637569C (es)
DK (1) DK1984009T3 (es)
ES (1) ES2397712T3 (es)
HK (1) HK1126975A1 (es)
MX (1) MX2008009125A (es)
RU (1) RU2427383C2 (es)
SI (1) SI1984009T1 (es)
WO (1) WO2007084460A2 (es)

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050124546A1 (en) * 1993-02-19 2005-06-09 Jurgen Engel Oligopeptide lyophilisate, their preparation and use
US20090169632A1 (en) * 2007-12-31 2009-07-02 Industrial Technology Research Institute Sustained release composition and manufacturing method thereof
US20090196905A1 (en) * 2008-02-06 2009-08-06 Spada Lon T Stabilization of mitochondrial membranes in ocular diseases and conditions
US20100266569A1 (en) * 2007-11-15 2010-10-21 Mark Zylka Prostatic acid phosphatase for the treatment of pain
US20110160134A1 (en) * 2008-06-16 2011-06-30 Q Chip Limited Device and Method for Making Solid Beads
CN102145160A (zh) * 2011-03-07 2011-08-10 深圳市健元医药科技有限公司 一种lhrh拮抗剂注射用的缓释植入制剂
US20120046225A1 (en) * 2010-07-19 2012-02-23 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
WO2012042274A1 (en) 2010-09-30 2012-04-05 Q Chip Limited Method of making solid beads
US20130157939A1 (en) * 2010-08-23 2013-06-20 Shmuel Ben-Sasson Compositions for gastric delivery of active agents
US20130157951A1 (en) * 2010-06-24 2013-06-20 Torrent Pharmaceuticals Limited Pharmaceutical Composition Containing Goserelin for In-Situ Implant
US8697644B2 (en) 2011-03-10 2014-04-15 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US20150010507A1 (en) * 2013-07-03 2015-01-08 Joseph Cummins System and Method for Treatment Using Orally Administered Interferon
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
US9044450B2 (en) 2005-09-30 2015-06-02 Durect Corporation Sustained release small molecule drug formulation
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US9138479B2 (en) 2011-10-31 2015-09-22 Xeris Pharmaceuticals, Inc. Formulations for the treatment of diabetes
US9156016B2 (en) 2010-09-30 2015-10-13 Midatech Pharma (Wales) Limited Apparatus and method for making solid beads
WO2016061296A1 (en) * 2014-10-15 2016-04-21 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition with improved stability
US9511146B2 (en) 2013-04-09 2016-12-06 International Business Machines Corporation Vitamin functionalized gel-forming block copolymers for biomedical applications
US9572812B2 (en) 2013-03-11 2017-02-21 Durect Corporation Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9737605B2 (en) 2013-03-11 2017-08-22 Durect Corporation Injectable controlled release composition comprising high viscosity liquid carrier
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9956164B2 (en) 2014-04-16 2018-05-01 Veyx-Pharma Gmbh Veterinary pharmaceutical composition and use thereof
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US10010612B2 (en) 2007-05-25 2018-07-03 Indivior Uk Limited Sustained delivery formulations of risperidone compounds
US10028957B2 (en) 2007-05-18 2018-07-24 Durect Corporation Depot formulations
US20180214507A1 (en) * 2017-01-31 2018-08-02 Veru Inc. COMPOSITIONS AND METHODS FOR LONG TERM RELEASE OF GONADOTROPIN-RELEASING HORMONE (GnRH) ANTAGONISTS
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10758623B2 (en) 2013-12-09 2020-09-01 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
WO2021092491A1 (en) * 2019-11-08 2021-05-14 Lyndra, Inc. Gastric residence systems for administration of active agents
US11020403B2 (en) 2017-06-02 2021-06-01 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
US11129940B2 (en) 2014-08-06 2021-09-28 Xeris Pharmaceuticals, Inc. Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
WO2006083761A2 (en) 2005-02-03 2006-08-10 Alza Corporation Solvent/polymer solutions as suspension vehicles
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
DK2020990T3 (da) 2006-05-30 2010-12-13 Intarcia Therapeutics Inc Strømningsmodulator med en indre kanal til et todelt osmotisk fremføringssystem
EP2049081B1 (en) 2006-08-09 2012-11-14 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies
EP1917971A1 (en) * 2006-10-27 2008-05-07 Société de Conseils de Recherches et d'Applications Scientifiques ( S.C.R.A.S.) Substained release formulations comprising very low molecular weight polymers
US8946200B2 (en) 2006-11-02 2015-02-03 Southwest Research Institute Pharmaceutically active nanosuspensions
CN101715340A (zh) * 2007-04-23 2010-05-26 精达制药公司 促胰岛素释放肽的混悬制剂及其应用
WO2009102467A2 (en) 2008-02-13 2009-08-20 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US8404850B2 (en) 2008-03-13 2013-03-26 Southwest Research Institute Bis-quaternary pyridinium-aldoxime salts and treatment of exposure to cholinesterase inhibitors
US8071537B2 (en) * 2008-06-25 2011-12-06 Endo Pharmaceuticals Solutions Inc. Implantable device for the sustained release of a polypeptide
US8722706B2 (en) 2008-08-15 2014-05-13 Southwest Research Institute Two phase bioactive formulations of bis-quaternary pyridinium oxime sulfonate salts
CN102958512B (zh) * 2008-08-29 2015-04-29 健赞股份有限公司 控释肽制剂
US8309134B2 (en) 2008-10-03 2012-11-13 Southwest Research Institute Modified calcium phosphate nanoparticle formation
JP5718925B2 (ja) 2009-09-28 2015-05-13 インターシア セラピューティクス，インコーポレイティド 実質的な定常状態薬物送達の迅速な確立及び／又は停止
JP5486690B2 (ja) 2009-11-16 2014-05-07 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ メラノコルチン受容体リガンドの医薬組成物
US9028873B2 (en) 2010-02-08 2015-05-12 Southwest Research Institute Nanoparticles for drug delivery to the central nervous system
ES2579941T3 (es) * 2010-03-15 2016-08-17 Ipsen Pharma S.A.S. Composiciones farmacéuticas de ligandos del receptor de secretagogos de la hormona del crecimiento
AU2011238646B2 (en) * 2010-03-29 2016-02-04 Evonik Corporation Compositions and methods for improved retention of a pharmaceutical composition at a local administration site
CN101810583B (zh) * 2010-04-09 2013-09-11 佟丽 Hiv融合抑制剂缓释微球
RU2446173C1 (ru) * 2010-08-13 2012-03-27 Зао "Биокад" Новый функционально активный, высокоочищенный стабильный конъюгат гранулоцитарного колониестимулирующего фактора (г-ксф) с полиэтиленгликолем с пролонгированным биологическим действием, пригодный для медицинского применения, и иммунобиологическое средство на его основе
CN101934068B (zh) * 2010-09-26 2012-07-25 武汉华龙生物制药有限公司 胸腺肽注射液的制备方法
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
CA2838917C (en) 2011-06-23 2016-10-18 British American Tobacco (Investments) Limited Filter material comprising polylactide fibres
GB201112402D0 (en) 2011-07-19 2011-08-31 British American Tobacco Co Cellulose acetate compositions
GB201208293D0 (en) 2012-05-11 2012-06-20 Circassia Ltd Hydrochlorice salt of peptide
US9757330B2 (en) 2013-10-18 2017-09-12 Industrial Technology Research Institute Recipe for in-situ gel, and implant, drug delivery system formed thereby
CN109498815B (zh) * 2013-12-30 2022-07-22 江苏众红生物工程创药研究院有限公司 重组人激肽释放酶的化学修饰物及其应用
KR102327754B1 (ko) * 2014-02-06 2021-11-17 엑스에리스 파머수티클스, 인크. 안정한 펩티드 제형물 및 제조 방법
RU2557925C1 (ru) * 2014-03-17 2015-07-27 Новиков Сергей Викторович Биодеградируемый многослойный имплант для введения лекарственных веществ в витреальную полость глаза
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
EP3206706A4 (en) * 2014-10-16 2018-05-30 Piramal Enterprises Limited Stable injectable composition of pharmaceutically active agents and process for its preparation
WO2016059592A1 (en) * 2014-10-16 2016-04-21 Piramal Enterprises Limited Stable injectable composition of peptide drugs and process for its preparation
US10046058B2 (en) 2014-12-02 2018-08-14 Rezolute, Inc. Use of hydrophobic organic acids to increase hydrophobicity of proteins and protein conjugates
WO2016196851A2 (en) 2015-06-03 2016-12-08 Intarcia Therapeutics, Inc. Implant placement and removal systems
BR112018002414B1 (pt) 2015-08-03 2023-11-21 Tolmar International Limited Composição farmacêutica de polímero líquido para administração no corpo de um animal, seu uso para tratar, prover uma terapia para curar ou prevenir uma doença, distúrbio ou outra enfermidade e sistema de distribuição para administração da dita composição
WO2017180781A1 (en) * 2016-04-12 2017-10-19 Trigemina, Inc. Magnesium-containing oxytocin formulations and methods of use
WO2017200943A1 (en) 2016-05-16 2017-11-23 Intarcia Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
KR20190104039A (ko) 2017-01-03 2019-09-05 인타르시아 세라퓨틱스 인코포레이티드 Glp-1 수용체 효능제의 연속적인 투여 및 약물의 동시-투여를 포함하는 방법
CN111511385B (zh) * 2017-12-18 2024-05-03 逸达生物科技股份有限公司 具有选定的释放持续时间的药物组合物
US20210205404A1 (en) * 2018-05-16 2021-07-08 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition of kor receptor agonist
CN109316371B (zh) * 2018-09-21 2021-09-03 珀莱雅化妆品股份有限公司 一种芹菜素缓释制剂的制备方法
KR20200051916A (ko) * 2018-11-05 2020-05-14 주식회사 메디포럼제약 고세렐린을 포함하는 실리카 하이드로겔 조성물
CN113631251A (zh) * 2019-03-15 2021-11-09 诺和诺德股份有限公司 Glp-1肽的喷雾干燥工艺
KR102249104B1 (ko) * 2019-04-30 2021-05-07 (주)인벤티지랩 데슬로렐린을 포함하는 서방성 마이크로 입자 및 이의 제조 방법
BR112021023904A2 (pt) * 2019-05-27 2022-02-01 Tolmar Int Ltd Composições de acetato de leuprolida e métodos de uso dos mesmos para tratar câncer de mama
US20220323603A1 (en) * 2019-06-07 2022-10-13 President And Fellows Of Harvard College Compositions and methods relating to erythrocytes with adhered particles
AU2022323754A1 (en) 2021-08-05 2024-02-08 Medincell S.A. Pharmaceutical composition

Citations (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US444340A (en) * 1891-01-06 Coupling-shoe
US4938763A (en) * 1988-10-03 1990-07-03 Dunn Richard L Biodegradable in-situ forming implants and methods of producing the same
US5004602A (en) * 1981-02-16 1991-04-02 Imperial Chemical Industries Plc Continuous release pharmaceutical compositions formed by freeze drying acetic acid solutions of polylactide
US5242910A (en) * 1992-10-13 1993-09-07 The Procter & Gamble Company Sustained release compositions for treating periodontal disease
US5310865A (en) * 1991-12-18 1994-05-10 Mitsui Toatsu Chemicals, Incorporated Polyhydroxycarboxylic acid and preparation process thereof
US5324519A (en) * 1989-07-24 1994-06-28 Atrix Laboratories, Inc. Biodegradable polymer composition
US5410016A (en) * 1990-10-15 1995-04-25 Board Of Regents, The University Of Texas System Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers
US5446090A (en) * 1993-11-12 1995-08-29 Shearwater Polymers, Inc. Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
US5487897A (en) * 1989-07-24 1996-01-30 Atrix Laboratories, Inc. Biodegradable implant precursor
US5501863A (en) * 1990-02-09 1996-03-26 Schering Aktiengesellschaft Contrast media synthesized from polyaldehydes
US5529914A (en) * 1990-10-15 1996-06-25 The Board Of Regents The Univeristy Of Texas System Gels for encapsulation of biological materials
US5681873A (en) * 1993-10-14 1997-10-28 Atrix Laboratories, Inc. Biodegradable polymeric composition
US5693609A (en) * 1994-11-17 1997-12-02 Eli Lilly And Company Acylated insulin analogs
US5698213A (en) * 1995-03-06 1997-12-16 Ethicon, Inc. Hydrogels of absorbable polyoxaesters
US5702716A (en) * 1988-10-03 1997-12-30 Atrix Laboratories, Inc. Polymeric compositions useful as controlled release implants
US5736152A (en) * 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5744153A (en) * 1994-04-08 1998-04-28 Atrix Laboratories, Inc. Liquid delivery compositions
US5750497A (en) * 1993-09-17 1998-05-12 Novo Nordisk A/S Acylated insulin
US5792469A (en) * 1992-03-12 1998-08-11 Atrix Laboratories, Inc. Biodegradable in situ forming film dressing
US5880255A (en) * 1988-10-20 1999-03-09 Polymasc Pharmaceuticals Plc Process for fractionating polyethylene glycol (PEG)-protein adducts and an adduct of PEG and granulocyte-macrophage colony stimulating factor
US5945115A (en) * 1991-10-15 1999-08-31 Atrix Laboratories, Inc. Polymeric compositions useful as controlled release implants
US6113906A (en) * 1993-10-27 2000-09-05 Enzon, Inc. Water-soluble non-antigenic polymer linkable to biologically active material
US6143314A (en) * 1998-10-28 2000-11-07 Atrix Laboratories, Inc. Controlled release liquid delivery compositions with low initial drug burst
US6217893B1 (en) * 1997-04-18 2001-04-17 Pharma Biotech Sustained-release compositions and method for preparing same
US6261583B1 (en) * 1998-07-28 2001-07-17 Atrix Laboratories, Inc. Moldable solid delivery system
US6312679B1 (en) * 1986-08-18 2001-11-06 The Dow Chemical Company Dense star polymer conjugates as dyes
US6355657B1 (en) * 1998-12-30 2002-03-12 Atrix Laboratories, Inc. System for percutaneous delivery of opioid analgesics
US6410044B1 (en) * 1998-03-19 2002-06-25 Surmodics, Inc. Crosslinkable macromers
US6461631B1 (en) * 1999-11-16 2002-10-08 Atrix Laboratories, Inc. Biodegradable polymer composition
US20020164365A1 (en) * 1995-04-13 2002-11-07 Shalaby Shalaby W. Multifaceted compositions for post-surgical adhesion prevention
USRE37950E1 (en) * 1990-04-24 2002-12-31 Atrix Laboratories Biogradable in-situ forming implants and methods of producing the same
US20030044463A1 (en) * 2001-09-06 2003-03-06 Romano Deghenghi Sustained release of microcrystalline peptide suspensions
US6565874B1 (en) * 1998-10-28 2003-05-20 Atrix Laboratories Polymeric delivery formulations of leuprolide with improved efficacy
US20030175285A1 (en) * 2000-03-23 2003-09-18 Christine Klinguer-Hamour Molecule of pharmaceutical interest comprising at its n-terminal a glutamic acid or a glutamine in the form of a physiologically acceptable strong acid
US20050042294A1 (en) * 2003-07-18 2005-02-24 Thanoo Bagavathikanun C. Prevention of molecular weight reduction of the polymer, impurity formation and gelling in polymer compositions
US20050272806A1 (en) * 2004-06-02 2005-12-08 Robert Falotico Injectable formulations of taxanes for cad treatment
US20060034923A1 (en) * 2004-08-12 2006-02-16 Quest Pharmaceutical Services Pharmaceutical compositions for controlled release delivery of biologically active compounds
US20090004273A1 (en) * 2003-12-30 2009-01-01 Durect Corporation Polymeric device for controlled release of active agents

Family Cites Families (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4443340A (en) 1981-10-09 1984-04-17 Betz Laboratories, Inc. Control of iron induced fouling in water systems
JP2551756B2 (ja) 1985-05-07 1996-11-06 武田薬品工業株式会社 ポリオキシカルボン酸エステルおよびその製造法
DE3708916A1 (de) 1987-03-19 1988-09-29 Boehringer Ingelheim Kg Verfahren zur reinigung resorbierbarer polyester
JPH0818999B2 (ja) * 1990-01-05 1996-02-28 藤沢薬品工業株式会社 インシュリン様成長因子ｉの乾燥製剤
DE69129770T2 (de) 1990-04-13 1998-11-19 Takeda Chemical Industries Ltd Biologisch abbaubare hochmolekulare Polymere, ihre Herstellung und ihre Verwendung
IE912365A1 (en) * 1990-07-23 1992-01-29 Zeneca Ltd Continuous release pharmaceutical compositions
US5338822A (en) 1992-10-02 1994-08-16 Cargill, Incorporated Melt-stable lactide polymer composition and process for manufacture thereof
JP2944419B2 (ja) * 1993-05-10 1999-09-06 ノバルティス アクチエンゲゼルシャフト 持続性遊離組成物中の薬理学的活性成分の安定
US5478921A (en) 1994-08-25 1995-12-26 United States Surgical Corporation Method of purifying bioabsorable polymer
US5869602A (en) 1995-03-17 1999-02-09 Novo Nordisk A/S Peptide derivatives
US7033608B1 (en) 1995-05-22 2006-04-25 The United States Of America As Represented By The Secretary Of The Army “Burst-free” sustained release poly-(lactide/glycolide) microspheres
WO1998008872A1 (en) 1996-08-30 1998-03-05 Novo Nordisk A/S Glp-2 derivatives
ATE356830T1 (de) 1996-08-30 2007-04-15 Novo Nordisk As Glp-1 derivate
US6126919A (en) 1997-02-07 2000-10-03 3M Innovative Properties Company Biocompatible compounds for pharmaceutical drug delivery systems
AU1519399A (en) * 1997-11-07 1999-05-31 Chiron Corporation Compositions providing for increased igf-i solubility
WO1999043708A1 (en) 1998-02-27 1999-09-02 Novo Nordisk A/S Glp-1 derivatives of glp-1 and exendin with protracted profile of action
DE19908753C2 (de) 1999-02-20 2003-10-02 Jenapharm Gmbh Bioabbaubare, injizierbare Oligomer-Polymer-Zusammensetzung
US6626870B1 (en) 2000-03-27 2003-09-30 Artix Laboratories, Inc. Stoppering method to maintain sterility
CN1269870C (zh) 2000-08-07 2006-08-16 和光纯药工业株式会社 乳酸聚合物及其制备方法
US8470359B2 (en) 2000-11-13 2013-06-25 Qlt Usa, Inc. Sustained release polymer
TWI225416B (en) 2001-06-29 2004-12-21 Takeda Chemical Industries Ltd Sustained-release composition and process for producing the same
TW200526267A (en) 2001-06-29 2005-08-16 Takeda Chemical Industries Ltd Controlled release composition and method of producing the same
US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
EP1526835B1 (en) 2002-07-31 2008-04-23 ALZA Corporation Injectable depot compositions and uses thereof
US6966990B2 (en) 2002-10-11 2005-11-22 Ferro Corporation Composite particles and method for preparing
UY28213A1 (es) 2003-02-28 2004-09-30 Bayer Pharmaceuticals Corp Nuevos derivados de cianopiridina útiles en el tratamiento de cáncer y otros trastornos.
US8313763B2 (en) 2004-10-04 2012-11-20 Tolmar Therapeutics, Inc. Sustained delivery formulations of rapamycin compounds
CA2586846C (en) 2004-11-10 2013-12-31 Qlt Usa Inc. A stabilized polymeric delivery system
ATE382337T1 (de) 2005-04-28 2008-01-15 Nipro Corp Bioabsorbierbare pharmazeutische zusammensetzung enthaltend einen plga-copolymer
CA2666341C (en) 2006-10-11 2012-01-03 Qlt Usa, Inc. Preparation of biodegradable polyesters with low-burst properties by supercritical fluid extraction
US8076448B2 (en) 2006-10-11 2011-12-13 Tolmar Therapeutics, Inc. Preparation of biodegradable polyesters with low-burst properties by supercritical fluid extraction
SI3202814T1 (sl) 2007-02-15 2019-12-31 Tolmar Therapeutics, Inc. Poli-(laktid/glikolid) z nizkim razpokom in postopki za proizvodnjo polimerov
EP2291174B1 (en) 2008-06-03 2015-01-28 Tolmar Therapeutics, Inc. Flowable composition comprising biocompatible oligomer-polymer compositions
CN102112107A (zh) 2008-06-03 2011-06-29 托马医疗科技公司 具有改进的释放动力学特征的控制释放共聚物制剂
CA2968989A1 (en) 2014-12-04 2016-06-09 Tolmar Therapeutics, Inc. Syringe plunger system with self-locking threaded geometry
BR112018002414B1 (pt) 2015-08-03 2023-11-21 Tolmar International Limited Composição farmacêutica de polímero líquido para administração no corpo de um animal, seu uso para tratar, prover uma terapia para curar ou prevenir uma doença, distúrbio ou outra enfermidade e sistema de distribuição para administração da dita composição

Patent Citations (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US444340A (en) * 1891-01-06 Coupling-shoe
US5004602A (en) * 1981-02-16 1991-04-02 Imperial Chemical Industries Plc Continuous release pharmaceutical compositions formed by freeze drying acetic acid solutions of polylactide
US6312679B1 (en) * 1986-08-18 2001-11-06 The Dow Chemical Company Dense star polymer conjugates as dyes
US5340849A (en) * 1988-10-03 1994-08-23 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods for producing the same
US4938763A (en) * 1988-10-03 1990-07-03 Dunn Richard L Biodegradable in-situ forming implants and methods of producing the same
US5278201A (en) * 1988-10-03 1994-01-11 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same
US5733950A (en) * 1988-10-03 1998-03-31 Atrix Laboratories, Incorporated Biodegradable in-situ forming implants and methods of producing the same
US5739176A (en) * 1988-10-03 1998-04-14 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same
US5702716A (en) * 1988-10-03 1997-12-30 Atrix Laboratories, Inc. Polymeric compositions useful as controlled release implants
US5990194A (en) * 1988-10-03 1999-11-23 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same
US4938763B1 (en) * 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
US5278202A (en) * 1988-10-03 1994-01-11 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same
US5880255A (en) * 1988-10-20 1999-03-09 Polymasc Pharmaceuticals Plc Process for fractionating polyethylene glycol (PEG)-protein adducts and an adduct of PEG and granulocyte-macrophage colony stimulating factor
US5487897A (en) * 1989-07-24 1996-01-30 Atrix Laboratories, Inc. Biodegradable implant precursor
US5324519A (en) * 1989-07-24 1994-06-28 Atrix Laboratories, Inc. Biodegradable polymer composition
US5599552A (en) * 1989-07-24 1997-02-04 Atrix Laboratories, Inc. Biodegradable polymer composition
US6395293B2 (en) * 1989-07-24 2002-05-28 Atrix Laboratories Biodegradable implant precursor
US5501863A (en) * 1990-02-09 1996-03-26 Schering Aktiengesellschaft Contrast media synthesized from polyaldehydes
USRE37950E1 (en) * 1990-04-24 2002-12-31 Atrix Laboratories Biogradable in-situ forming implants and methods of producing the same
US5529914A (en) * 1990-10-15 1996-06-25 The Board Of Regents The Univeristy Of Texas System Gels for encapsulation of biological materials
US5410016A (en) * 1990-10-15 1995-04-25 Board Of Regents, The University Of Texas System Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers
US5945115A (en) * 1991-10-15 1999-08-31 Atrix Laboratories, Inc. Polymeric compositions useful as controlled release implants
US5310865A (en) * 1991-12-18 1994-05-10 Mitsui Toatsu Chemicals, Incorporated Polyhydroxycarboxylic acid and preparation process thereof
US5792469A (en) * 1992-03-12 1998-08-11 Atrix Laboratories, Inc. Biodegradable in situ forming film dressing
US5242910A (en) * 1992-10-13 1993-09-07 The Procter & Gamble Company Sustained release compositions for treating periodontal disease
US5750497A (en) * 1993-09-17 1998-05-12 Novo Nordisk A/S Acylated insulin
US5681873A (en) * 1993-10-14 1997-10-28 Atrix Laboratories, Inc. Biodegradable polymeric composition
US6113906A (en) * 1993-10-27 2000-09-05 Enzon, Inc. Water-soluble non-antigenic polymer linkable to biologically active material
US5446090A (en) * 1993-11-12 1995-08-29 Shearwater Polymers, Inc. Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
US5744153A (en) * 1994-04-08 1998-04-28 Atrix Laboratories, Inc. Liquid delivery compositions
US5780044A (en) * 1994-04-08 1998-07-14 Atrix Laboratories, Inc. Liquid delivery compositions
US5759563A (en) * 1994-04-08 1998-06-02 Atrix Laboratories, Inc. Liquid delivery compositions
US5693609A (en) * 1994-11-17 1997-12-02 Eli Lilly And Company Acylated insulin analogs
US5698213A (en) * 1995-03-06 1997-12-16 Ethicon, Inc. Hydrogels of absorbable polyoxaesters
US20020164365A1 (en) * 1995-04-13 2002-11-07 Shalaby Shalaby W. Multifaceted compositions for post-surgical adhesion prevention
US5736152A (en) * 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US6217893B1 (en) * 1997-04-18 2001-04-17 Pharma Biotech Sustained-release compositions and method for preparing same
US6410044B1 (en) * 1998-03-19 2002-06-25 Surmodics, Inc. Crosslinkable macromers
US6261583B1 (en) * 1998-07-28 2001-07-17 Atrix Laboratories, Inc. Moldable solid delivery system
US6143314A (en) * 1998-10-28 2000-11-07 Atrix Laboratories, Inc. Controlled release liquid delivery compositions with low initial drug burst
US6565874B1 (en) * 1998-10-28 2003-05-20 Atrix Laboratories Polymeric delivery formulations of leuprolide with improved efficacy
US6773714B2 (en) * 1998-10-28 2004-08-10 Atrix Laboratories, Inc. Polymeric delivery formulations of leuprolide with improved efficacy
US6355657B1 (en) * 1998-12-30 2002-03-12 Atrix Laboratories, Inc. System for percutaneous delivery of opioid analgesics
US6461631B1 (en) * 1999-11-16 2002-10-08 Atrix Laboratories, Inc. Biodegradable polymer composition
US6528080B2 (en) * 1999-11-16 2003-03-04 Atrix Laboratories, Inc. Biodegradable polymer composition
US20030175285A1 (en) * 2000-03-23 2003-09-18 Christine Klinguer-Hamour Molecule of pharmaceutical interest comprising at its n-terminal a glutamic acid or a glutamine in the form of a physiologically acceptable strong acid
US20030044463A1 (en) * 2001-09-06 2003-03-06 Romano Deghenghi Sustained release of microcrystalline peptide suspensions
US20050042294A1 (en) * 2003-07-18 2005-02-24 Thanoo Bagavathikanun C. Prevention of molecular weight reduction of the polymer, impurity formation and gelling in polymer compositions
US20090004273A1 (en) * 2003-12-30 2009-01-01 Durect Corporation Polymeric device for controlled release of active agents
US20050272806A1 (en) * 2004-06-02 2005-12-08 Robert Falotico Injectable formulations of taxanes for cad treatment
US20060034923A1 (en) * 2004-08-12 2006-02-16 Quest Pharmaceutical Services Pharmaceutical compositions for controlled release delivery of biologically active compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Bastin et al. in Organic Process Research & Development 2000, 4, 427 - 435 *

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7605121B2 (en) * 1993-02-19 2009-10-20 Aeterna Zentaris Gmbh Oligopeptide lyophilisate, their preparation and use
US20050124546A1 (en) * 1993-02-19 2005-06-09 Jurgen Engel Oligopeptide lyophilisate, their preparation and use
US11110093B2 (en) 2005-09-30 2021-09-07 Indivior Uk Limited Sustained release small molecule drug formulation
US9597402B2 (en) 2005-09-30 2017-03-21 Durect Corporation Sustained release small molecule drug formulation
US9044450B2 (en) 2005-09-30 2015-06-02 Durect Corporation Sustained release small molecule drug formulation
US10058554B2 (en) 2005-09-30 2018-08-28 Indivior Uk Limited Sustained release small molecule drug formulation
US10028957B2 (en) 2007-05-18 2018-07-24 Durect Corporation Depot formulations
US11712475B2 (en) 2007-05-25 2023-08-01 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US10376590B2 (en) 2007-05-25 2019-08-13 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US10010612B2 (en) 2007-05-25 2018-07-03 Indivior Uk Limited Sustained delivery formulations of risperidone compounds
US11013809B2 (en) 2007-05-25 2021-05-25 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US20100266569A1 (en) * 2007-11-15 2010-10-21 Mark Zylka Prostatic acid phosphatase for the treatment of pain
US9161943B2 (en) * 2007-12-31 2015-10-20 Industrial Technology Research Institute Sustained release composition and manufacturing method thereof
US20090169632A1 (en) * 2007-12-31 2009-07-02 Industrial Technology Research Institute Sustained release composition and manufacturing method thereof
US20090196905A1 (en) * 2008-02-06 2009-08-06 Spada Lon T Stabilization of mitochondrial membranes in ocular diseases and conditions
US20110160134A1 (en) * 2008-06-16 2011-06-30 Q Chip Limited Device and Method for Making Solid Beads
US9656228B2 (en) 2008-06-16 2017-05-23 Midatech Pharma (Wales) Limited Device and method for making solid beads
US9364518B2 (en) * 2010-06-24 2016-06-14 Torrent Pharmaceuticals Limited Pharmaceutical composition containing goserelin for in-situ implant
US20130157951A1 (en) * 2010-06-24 2013-06-20 Torrent Pharmaceuticals Limited Pharmaceutical Composition Containing Goserelin for In-Situ Implant
US9687527B2 (en) 2010-07-19 2017-06-27 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
US20120046225A1 (en) * 2010-07-19 2012-02-23 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
US20130157939A1 (en) * 2010-08-23 2013-06-20 Shmuel Ben-Sasson Compositions for gastric delivery of active agents
US9259701B2 (en) 2010-09-30 2016-02-16 Q Chip Ltd. Method for making solid beads
US9156016B2 (en) 2010-09-30 2015-10-13 Midatech Pharma (Wales) Limited Apparatus and method for making solid beads
WO2012042274A1 (en) 2010-09-30 2012-04-05 Q Chip Limited Method of making solid beads
CN102145160A (zh) * 2011-03-07 2011-08-10 深圳市健元医药科技有限公司 一种lhrh拮抗剂注射用的缓释植入制剂
US9295724B2 (en) 2011-03-10 2016-03-29 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US10987399B2 (en) 2011-03-10 2021-04-27 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US8697644B2 (en) 2011-03-10 2014-04-15 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9339545B2 (en) 2011-03-10 2016-05-17 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9302010B2 (en) 2011-03-10 2016-04-05 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9138479B2 (en) 2011-10-31 2015-09-22 Xeris Pharmaceuticals, Inc. Formulations for the treatment of diabetes
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US10765683B2 (en) 2012-06-27 2020-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US11446310B2 (en) 2012-06-27 2022-09-20 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
US9642894B2 (en) 2013-02-06 2017-05-09 Xeris Pharmaceuticals, Inc. Compositions for rapidly treating severe hypoglycemia
US9737605B2 (en) 2013-03-11 2017-08-22 Durect Corporation Injectable controlled release composition comprising high viscosity liquid carrier
US11285217B2 (en) 2013-03-11 2022-03-29 Durect Corporation Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material
US9572812B2 (en) 2013-03-11 2017-02-21 Durect Corporation Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material
US10226532B2 (en) 2013-03-11 2019-03-12 Durect Corporation Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material
US9511146B2 (en) 2013-04-09 2016-12-06 International Business Machines Corporation Vitamin functionalized gel-forming block copolymers for biomedical applications
US9637592B2 (en) 2013-04-09 2017-05-02 International Business Machines Corporation Vitamin functionalized gel-forming block copolymers for biomedical applications
US9642893B2 (en) * 2013-07-03 2017-05-09 Joseph Cummins Method for reducing injury and stabilizing muscle using orally administered interferon
US20150010507A1 (en) * 2013-07-03 2015-01-08 Joseph Cummins System and Method for Treatment Using Orally Administered Interferon
US10758623B2 (en) 2013-12-09 2020-09-01 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
US11529420B2 (en) 2013-12-09 2022-12-20 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9956164B2 (en) 2014-04-16 2018-05-01 Veyx-Pharma Gmbh Veterinary pharmaceutical composition and use thereof
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US11129940B2 (en) 2014-08-06 2021-09-28 Xeris Pharmaceuticals, Inc. Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes
WO2016061296A1 (en) * 2014-10-15 2016-04-21 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition with improved stability
US20220160817A1 (en) * 2014-10-15 2022-05-26 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition with improved stability
KR102134873B1 (ko) 2014-10-15 2020-07-17 위후아 리 향상된 안정성을 갖는 약제학적 조성물
RU2728786C2 (ru) * 2014-10-15 2020-07-31 Фореси Фармасьютикалс Ко., Лтд. Фармацевтическая композиция с улучшенной стабильностью
KR20170070176A (ko) * 2014-10-15 2017-06-21 위후아 리 향상된 안정성을 갖는 약제학적 조성물
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US10485850B2 (en) 2015-09-25 2019-11-26 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
EP4011386A1 (en) * 2017-01-31 2022-06-15 Veru Inc. Compositions and methods for long term release of gonadotropin-releasing hormone (gnrh) antagonists
CN110234336A (zh) * 2017-01-31 2019-09-13 维鲁公司 用于促性腺激素释放激素(GnRH)拮抗剂的长效释放的组合物和方法
WO2018144603A1 (en) * 2017-01-31 2018-08-09 Veru Inc. COMPOSITIONS AND METHODS FOR LONG TERM RELEASE OF GANADOTROPIN-RELEASING HORMONE (GnRH) ANTAGONISTS
US20180214507A1 (en) * 2017-01-31 2018-08-02 Veru Inc. COMPOSITIONS AND METHODS FOR LONG TERM RELEASE OF GONADOTROPIN-RELEASING HORMONE (GnRH) ANTAGONISTS
US11020403B2 (en) 2017-06-02 2021-06-01 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
US11833157B2 (en) 2017-06-02 2023-12-05 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
WO2021092491A1 (en) * 2019-11-08 2021-05-14 Lyndra, Inc. Gastric residence systems for administration of active agents

Also Published As

Publication number Publication date
US20160331802A1 (en) 2016-11-17
RU2008129201A (ru) 2010-02-27
CN101400363A (zh) 2009-04-01
US20180050108A1 (en) 2018-02-22
CA2637569C (en) 2013-01-08
RU2427383C2 (ru) 2011-08-27
AU2007207618B2 (en) 2011-03-24
WO2007084460A8 (en) 2008-09-04
US20190231881A1 (en) 2019-08-01
US10646572B2 (en) 2020-05-12
EP1984009A4 (en) 2009-08-05
ES2397712T3 (es) 2013-03-08
KR20080089643A (ko) 2008-10-07
WO2007084460A3 (en) 2007-11-08
US10251956B2 (en) 2019-04-09
SI1984009T1 (sl) 2013-02-28
US9744207B2 (en) 2017-08-29
CN101400363B (zh) 2012-08-29
AU2007207618A1 (en) 2007-07-26
EP1984009B1 (en) 2012-10-24
KR101728868B1 (ko) 2017-05-02
KR20150017777A (ko) 2015-02-17
EP1984009A2 (en) 2008-10-29
DK1984009T3 (da) 2013-01-28
HK1126975A1 (en) 2009-09-18
BRPI0706558A2 (pt) 2011-03-29
JP2009523798A (ja) 2009-06-25
US20170119842A1 (en) 2017-05-04
US9572857B2 (en) 2017-02-21
CA2637569A1 (en) 2007-07-26
JP5242415B2 (ja) 2013-07-24
MX2008009125A (es) 2008-10-23
WO2007084460A2 (en) 2007-07-26

Similar Documents

Publication Publication Date Title
US10646572B2 (en) Pharmaceutical compositions with enhanced stability
US20230346877A1 (en) Pharmaceutical Compositions having a Selected Release Duration
NZ766167B2 (en) Pharmaceutical compositions having a selected release duration
BRPI0706558B1 (pt) Composição polimérica injetável, métodos para preparar uma composição polimérica injetável e métodos para preparar um sal de um análogo de hormônio de liberação de hormônio luteínico (lhrh)
TWI376241B (en) Pharmaceutical compositions with enhanced stability
EP2172189A1 (en) Pharmaceutical Compositions

Legal Events

Date Code Title Description
AS Assignment

Owner name: QUEST PHARMACEUTICAL SERVICES, LLC, DELAWARE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LI, YUHUA;CHIEN, BENJAMIN;REEL/FRAME:019141/0090;SIGNING DATES FROM 20070205 TO 20070219

AS Assignment

Owner name: QPS, LLC, DELAWARE

Free format text: CHANGE OF NAME;ASSIGNOR:QUEST PHARMACEUTICAL SERVICES, LLC;REEL/FRAME:020451/0887

Effective date: 20071203

AS Assignment

Owner name: CAPITALSOURCE CF LLC, AS AGENT, MARYLAND

Free format text: SECURITY AGREEMENT;ASSIGNOR:QPS, LLC;REEL/FRAME:020487/0009

Effective date: 20080204

AS Assignment

Owner name: QPS, LLC, DELAWARE

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:CAPITALSOURCE CF LLC;REEL/FRAME:027061/0812

Effective date: 20090720

Owner name: BIO-KINETIC CLINICAL APPLICATIONS, LLC, DELAWARE

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:CAPITALSOURCE CF LLC;REEL/FRAME:027061/0812

Effective date: 20090720

Owner name: QPS HOLDINGS, LLC, DELAWARE

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:CAPITALSOURCE CF LLC;REEL/FRAME:027061/0812

Effective date: 20090720

Owner name: FORESEE PHARMACEUTICALS, LLC, DELAWARE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:QPS, LLC;REEL/FRAME:027067/0001

Effective date: 20110802

AS Assignment

Owner name: FORESEEACER PHARMACEUTICALS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FORESEE PHARMACEUTICALS, LLC;REEL/FRAME:029783/0514

Effective date: 20130131

AS Assignment

Owner name: FORESEEACER PHARMACEUTICALS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FORESEE PHARMACEUTICALS, LLC;REEL/FRAME:030244/0556

Effective date: 20130227

AS Assignment

Owner name: FORESEE PHARMACEUTICALS CO., LTD., TAIWAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FORESEEACER PHARMACEUTICALS, INC.;REEL/FRAME:035479/0878

Effective date: 20150420

STCB Information on status: application discontinuation

Free format text: ABANDONED -- AFTER EXAMINER'S ANSWER OR BOARD OF APPEALS DECISION