US20090181068A1 - Low Viscosity Liquid Polymeric Delivery System - Google Patents

Low Viscosity Liquid Polymeric Delivery System Download PDF

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Publication number
US20090181068A1
US20090181068A1 US12/100,562 US10056208A US2009181068A1 US 20090181068 A1 US20090181068 A1 US 20090181068A1 US 10056208 A US10056208 A US 10056208A US 2009181068 A1 US2009181068 A1 US 2009181068A1
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United States
Prior art keywords
composition
liquid
solvent
polymer
liquid polymer
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
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US12/100,562
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English (en)
Inventor
Richard L. Dunn
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.)
Dunn Research & Consulting LLC
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Dunn Research & Consulting 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
Application filed by Dunn Research & Consulting LLC filed Critical Dunn Research & Consulting LLC
Priority to US12/100,562 priority Critical patent/US20090181068A1/en
Assigned to DUNN RESEARCH & CONSULTING, LLC reassignment DUNN RESEARCH & CONSULTING, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DUNN, RICHARD L.
Priority to CA2787097A priority patent/CA2787097C/en
Priority to SI200930120T priority patent/SI2244752T1/sl
Priority to AT09702328T priority patent/ATE526046T1/de
Priority to PL09702328T priority patent/PL2244752T3/pl
Priority to PCT/US2009/030853 priority patent/WO2009091737A2/en
Priority to CA2714757A priority patent/CA2714757C/en
Priority to EP09702328A priority patent/EP2244752B1/de
Priority to PT09702328T priority patent/PT2244752E/pt
Priority to US12/812,670 priority patent/US8187640B2/en
Priority to ES09702328T priority patent/ES2370377T3/es
Priority to EP11005377A priority patent/EP2371400A3/de
Publication of US20090181068A1 publication Critical patent/US20090181068A1/en
Priority to HK11104383.4A priority patent/HK1150982A1/xx
Priority to CY20111101262T priority patent/CY1113604T1/el
Priority to US13/429,890 priority patent/US20120183629A1/en
Abandoned legal-status Critical Current

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Definitions

  • Embodiments of the present invention relate to methods and compositions for producing low viscosity biodegradable polymer solutions comprising liquid biodegradable polymers and biocompatible solvent that can be easily administered to the body where the biocompatible solvent dissipates in body fluid leaving a liquid polymer implant.
  • the biodegradable liquid polymer implants are suitable for the delivery of biologically active agents and for use as medical or surgical devices.
  • Biodegradable polymers are well known for their use in biomedical applications such as sutures, surgical clips, staples, implants, and drug delivery systems. These polymers include the polyglycolides, polylactides, polycaprolactones, polyanhydrides, polyorthoesters, polydioxanones, polyacetals, polyesteramides, polyamides, polyurethanes, polycarbonates, poly(amino acids), polyphosphazenes, polyketals, polyhydroxybutyrates, polyhydroxyalerates, and polyalkylene oxalates. Examples of their uses are described in U.S. Pat. No. 3,297,033 to Schmitt, U.S. Pat. No. 3,636,956 to Schneider, U.S.
  • biodegradable polymers described in the foregoing patents are solid materials used to form solid articles such as sutures, staples, surgical clips, implants or microcapsules and microparticles. Because these polymers are solids, all of their applications in the biomedical field require that the polymeric structures be formed outside the body, and then inserted into the body for their use. Sutures, clips, and staples are normally placed in the body during a surgical procedure. Solid implants for drug delivery are either surgically placed or inserted into the body using large diameter trochars. Only the microparticles including microcapsules and microspheres can be injected using standard syringes and needles.
  • microparticles and nanoparticles are a difficult process with many variables that have to be controlled to obtain reproducible drug delivery systems. These include solvent selection, polymer and drug concentration, temperature, stirring speed, drug loading, particle size, coating uniformity, and porosity. Because the drug is in contact with the polymer during the manufacturing steps and on storage, sterility and stability issues are normally encountered. In addition, a great deal of the drug is lost if the encapsulation efficiency is not high during the manufacturing process.
  • the present invention relates to compositions composed of liquid biodegradable polymers combined with biocompatible organic solvents and the use of the polymer compositions, for example, as drug delivery systems or medical or surgical devices.
  • liquid biodegradable polymers are dissolved in nontoxic biocompatible organic solvents to form low viscosity solutions that can be easily injected into the body with standard syringes and small gauge needles. Once the liquid polymer solution is placed within the body, the solvent dissipates or diffuses away from the polymer leaving a more viscous liquid polymer implant suitable, for example, for delivery of a biologically active agent or for use as a medical or surgical device. Because the polymer composition is a low viscosity liquid, it can be injected into muscle or subcutaneous tissue without damage to the surrounding tissue and without the noticeable bump observed with solid implants.
  • the liquid polymer/solvent composition can be used to form a medical or surgical implant by injection directly into a tissue site where the material will form a polymer film or coating, plug or other structure that remains in a liquid form or consistency after the solvent has dissipated.
  • the liquid polymer in the form of a film can be used, for example, to separate tissues to prevent the formation of surgical adhesions.
  • the liquid polymer/solvent composition can also be used to coat or cover an in-dwelling catheter or other device.
  • the liquid polymer/solvent composition can also be applied to form a plug or other liquid mass that can be used, for example, to temporarily seal tissue tears or holes.
  • the liquid polymer/solvent composition can be used as a system for delivery of a biologically active agent (e.g., drug), which can be dissolved or dispersed into the liquid polymer/biocompatible solvent solution.
  • a biologically active agent e.g., drug
  • the organic solvent upon exposure to an aqueous medium (e.g., body fluids) will dissolve or diffuse away from the liquid polymer component leaving a viscous liquid polymer implant with the active agent entrapped or encapsulated therein.
  • the hydrophilic or hydrophobic characteristic of the liquid polymer combined with its rate of degradation within the body can be used to control the release of the active agent over a desired time period.
  • An embodiment of a method according to the invention includes administering to a subject (e.g., patient) in need of a treatment or prevention, for example, an effective amount of the liquid polymer/solvent composition of the present invention, optionally with a bioactive agent.
  • Another embodiment of a method of the invention includes applying the liquid polymer/solvent composition, optionally with a bioactive agent, to a device such as a catheter, and inserting the coated device into the body of a subject for a desired treatment or procedure.
  • the present liquid polymer/solvent compositions provide the advantages of liquid application to form medical or surgical devices and/or delivery systems for active agents (e.g., drugs).
  • the present liquid polymer/solvent compositions also allow the use of smaller gauge needles compared to other liquid polymer systems made without a solvent.
  • the solvents used in the present compositions allow an active agent to also be administered as a solution in contrast to liquid polymer systems made without solvents.
  • the use of liquid biodegradable polymers in the present system also allows the rate of release of an active agent and degradation of the liquid implant to be varied over a wide range in contrast to the nonpolymeric liquid implant systems.
  • compositions of the present invention relate to solutions of a biodegradable liquid polymer(s) combined with a biocompatible organic solvent(s) that dissolves or dissipates when the liquid polymer/solvent compositions are placed in a body to form a viscous liquid polymer material in the form of a film, a coating, a plug or other mass.
  • the implanted polymer compositions can be used, for example, as a medical or surgical device and/or a delivery system for a biologically active agent (e.g., drug).
  • liquid refers to the ability of the composition and/or the liquid polymer materials to undergo continuous deformation under a shearing stress. As a liquid, the liquid polymer materials have a definite volume, but no definite shape.
  • polymer refers generally to polymers, copolymers and/or terpolymers that can be linear, branched, grafted and/or star-shaped.
  • liquid polymers combined with biocompatible organic solvents to form implants would release a drug or other active agent too fast to provide any sustained activity because of the rapid diffusion of the active agent through a liquid matrix rather than a solid matrix when placed into the body.
  • present liquid polymer/solvent solutions form implants that do not solidify and remain as a viscous liquid form upon injection into the body while providing comparable initial burst and sustained release of drugs and other active agents as implants formed from solid polymer/solvent solutions.
  • the present combination of liquid biodegradable polymers with biocompatible solvents provides readily injected and sterile filterable formulations.
  • the liquid implant material is biocompatible and allows the formulation to be injected into body tissue without tissue irritation and noticeable bumps associated with solid implants.
  • compositions are prepared by mixing or blending together the liquid polymer(s) and the organic solvent(s), which can be performed by any method at a temperature ranging from about 10-50° C. (e.g., at about 25° C.) using a suitable device to achieve a homogeneous, flowable liquid at room temperature.
  • suitable devices include a mechanical stirrer, a mixer, or a roller mill. Because both the polymer and solvents are liquids, they are readily mixed to form a homogeneous solution.
  • the liquid polymers that can be used according to the present invention are biodegradable and/or bioabsorbable, remain in a liquid (flowable) form at room temperature (i.e., at 25° C.) up to body temperature (i.e., at 37° C.), and have an intrinsic viscosity that allows the composition to be easily administered, and in some embodiments effective to provide a desired controlled release profile of a biologically active agent. Because the liquid polymer materials are already liquids at room temperature, they allow the use of lower concentrations of the biocompatible solvent to be used in the composition to provide a syringeable formulation than polymer/solvent compositions prepared with solid polymers.
  • suitable polymers which can be used in this application include polylactic acid, polyglycolic acid, polylactide (dl-lactide, d-lactide, l-lactide), polyglycolide, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), polyethylene glycol, hyaluronic acid, chitin and chitosan, and copolymers, terpolymers, and combinations or mixtures of the above materials.
  • Preferred materials include those polymers, copolymer or terpolymers made with lactide, glycolide, caprolactone, p-dioxanone, trimethylene carbonate, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one, ethylene oxide, propylene oxide, sebacic anhydride, diketene acetals/diols, and lactic acid with lower molecular weights and amorphous regions to limit crystallinity and subsequent solidification.
  • Solvents that can be used according to the invention are non-toxic and can be either hydrophilic or lipophilic depending upon the desired release profile and the solubility of the polymer and/or biologically active agent in the polymer/solvent composition.
  • a hydrophilic organic solvent will quickly dissolve in body fluids leaving the liquid polymer material as an implant, for example, in the form of a film, coating or plug. If a drug or other active agent is dissolved in a liquid polymer/hydrophilic solvent composition, the active agent will become encapsulated or entrapped in the liquid polymer material as the hydrophilic solvent dissolves or dissipates into the body fluid.
  • a lipophilic solvent when used, the dissolution or diffusion of the lipophilic solvent into surrounding aqueous tissue fluid will be relatively slow with a resultant slower increase in viscosity of the administered polymer/solvent composition.
  • a lipophilic solvent by its own nature, will slow the release of a biological active agent incorporated into the composition until the solvent has dissipated, leaving the liquid polymer implant with the entrapped active agent.
  • the release of the biologically active agent can be controlled to provide a low initial burst and sustained release of both hydrophilic and lipophilic drugs (or other active agent).
  • the solubility of a hydrophilic or lipophilic biologically active agent can be controlled to provide either solutions or dispersions of the active agent in the liquid polymer/solvent compositions.
  • Suitable hydrophilic biocompatible organic solvents that can be used according to the present invention have a water solubility greater than 10% by weight of the solvent in water.
  • hydrophilic biocompatible organic solvents include amides such as N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, N-ethyl-2-pyrrolidone, N-cycylohexyl-2-pyrrolidone, N-hydroxyethyl-2-pyrrolidone, dimethyl acetamide, and dimethyl formamide; acids such as acetic acid and lactic acid; alcohols such as ethanol and propanol; esters of monobasic acids such as methyl lactate, ethyl lactate, and methyl acetate; ether alcohols such as diethylene glycol monomethyl ether, glycofurol, glycerol formal, and isopropylidene glycerol (Solketal); sulfoxides such as dimethyl sulfoxide; lactones such
  • Preferred hydrophilic solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide, ethyl lactate, glycofurol, glycerol formal, isopropylidene glycerol, propylene glycol, polyethylene glycol, methoxypolyethylene glycol and methoxypropylene glycol due to their solvating ability and tissue compatibility.
  • Suitable lipophilic biocompatible organic solvents that can be used according to the invention have a water solubility less than 10% by weight of the solvent in water.
  • lipophilic biocompatible organic solvents include esters of mono-, di-, and tricarboxylic acids such as ethyl acetate, ethyl butyrate, ethyl oleate, isopropyl palmitate, ethyl palmitate, methyl palmitate, isopropyl myristate, diethyl malonate, diethyl succinate, dimethyl adipate, dimethyl succinate, dibutyl sebacate, triacetin, triethyl citrate, tributyrin, acetyl triethyl citrate, acetyl tributyl citrate, acetyl trihexyl citrate, butyryl trihexyl citrate, and tributyl citrate; esters of caprylic and/or capric acids with g
  • Preferred lipophilic solvents include ethyl acetate, ethyl oleate, isopropyl myristate, triacetin, triethyl citrate, acetyl tributyl citrate, ethyl benzoate, benzyl benzoate, and sesame oil.
  • Combinations of different hydrophilic solvents can be used to obtain higher or lower levels of solubility of the liquid polymer and bioactive agent in the resultant solution.
  • a combination of organic solvents can also be used to control the rate of release of an active agent by controlling the rate at which the solvent dissolves or dissipates when the liquid polymer/solvent/active agent composition is placed in the body.
  • combinations of different lipophilic solvents can also be used to control the solubility of the liquid polymer and active agent in the solvent and the release of the active agent in the body.
  • combinations of hydrophilic and lipophilic solvents can be used to obtain the optimum solvent characteristics for a delivery system.
  • Examples include a combination of N-methylpyrrolidone and triacetin which provides a more hydrophobic solvent than N-methylpyrrolidone alone, and a combination of N-methylpyrrolidone and ethanol which provides a more hydrophilic solvent than N-methylpyrrolidone alone.
  • the organic solvent is typically added to the compositions in an amount ranging from about 10 percent to about 70 percent by weight, relative to the total weight of the composition.
  • the solvent is present in the composition in an amount ranging from about 30 percent to about 50 percent by weight.
  • the concentration of solvent allows for the level of liquid polymer in the composition to range from about 30 percent to about 90 percent by weight, and preferably from about 50 percent to about 70 percent by weight relative to the overall composition.
  • the liquid polymer/solvent concentrations permit the liquid polymer/solvent compositions to be easily injected with standard syringes and small gauge needles (e.g., about 18-26 gauge) unlike liquid polymer formulations previously described, for example, by Bezwada and Scopelianos.
  • the compositions can be administered into the body of a human subject or animal such as a dog, cat, horse, etc.
  • the composition can be applied or injected into the body of a subject or onto an object (e.g., mesh, catheter, a screw, plate, tack, pin, staple, sponge, etc.) using a device such as a syringe or needle.
  • a device with the composition thereon can be placed into the body of the subject.
  • the liquid polymer component of the implanted polymer/solvent compositions of the invention will flow and fill the voids left by the organic solvent as it dissipates from the implanted material.
  • the implanted liquid polymer material remains as a liquid or fluid (flowable) consistency but not a gelatinous or solid consistency nor a microporous solid or gelatinous matrix.
  • the liquid polymer implant gradually biodegrades in the subject's body over time.
  • the liquid polymer/solvent compositions can be used, for example, for a variety of medical and surgical applications.
  • the liquid polymer/solvent compositions can be injected into or applied to soft tissue or surgical meshes to form a protective coating or film to prevent or minimize the formation of tissue adhesions.
  • the compositions can also be applied as films, for example, to coat vascular grafts to prevent the formation of blood clots, as liquid plugs, for example, to seal fluid or air leaks, or as an injected material, for example, to repair or augment a body tissue.
  • the liquid polymer/solvent compositions can be injected, for example, into facial tissues using small gauge needles to camouflage scars, fill depressions, and smooth out irregularities.
  • the compositions can also be applied to restore or improve sphincter function, and as general purpose fillers in the body.
  • the liquid polymer/solvent compositions can be used as controlled release implants to provide a delivery system in which a drug or other biologically active agent is added to the liquid polymer/solvent composition prior to injection in the body.
  • the organic solvent dissolves or dissipates in the aqueous tissue fluid to leave the more viscous liquid polymer for release of the encapsulated or entrapped active agent.
  • liquid polymer implant formed from compositions of the present invention by the dissolution or dissipation of the solvent can be used to control the release of biologically active agents.
  • the rate of release of the active agent can be controlled by the composition of the biodegradable polymer and/or by the hydrophilicity or lipophilicity of the organic solvent that is used.
  • the composition of the liquid polymer i.e., the type of monomer used or the ratio of monomers for copolymers or terpolymers, the end groups on the polymer chains, and the molecular weight of the polymer
  • More hydrophilic liquid polymers e.g., polylactic acid
  • more hydrophilic solvents e.g., N-methyl-2-pyrrolidone
  • more hydrophobic and slower degrading liquid polymers e.g., polycaprolactone
  • more lipophilic solvents e.g., triacetin
  • the active agent itself can be made more water-insoluble by utilizing active agents, for example, in the form of lipophilic salts, drug complexes, and/or prodrug esters, amides or ethers.
  • active agents for example, in the form of lipophilic salts, drug complexes, and/or prodrug esters, amides or ethers.
  • various forms of the drug or other biologically active agent can be used as needed.
  • the liquid polymer implant releases an effective amount of the bioactive agent by diffusion or dissolution from the liquid implant as it biodegrades in the body.
  • biologically active agent refers to a drug or other substance that provides a biological effect and acts locally or systemically in the treatment, therapy, cure and/or prevention of a disease, disorder or other ailment.
  • Representative biologically active agents include, without limitation, antibiotics, antimicrobials, anti-infectives, antigens, anti-allergenics, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, anti-tumor agents, anticancer drugs, decongestants, miotics, anti-cholinergics, sympathomimetics, sedatives, hypnotics, psychic energizers, tranquilizers, androgenic steroids, estrogens, progestational agents, LHRH agonists and antagonists, somatotropins, narcotic antagonists, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardioactive agents, antiparkinsonian agents, antihyposis, antiprolifer, pro
  • biologically-active agents include cisplatin, carboplatin, anastozole, fulvestrant, exemestane, estradiol, testosterone, misoprostol, follicle-stimulating hormone, dustasteride, doxycycline, ciprofloxacin, quinolone, ivermectin, haloperidol, diazepam, risperidone, olanzapine, naltrexone, fentanyl, buprenorphine, butorphanol, loperamide, nafarelin, buserelin, histrelin, deslorelin, leuprolide, goserelin, triptorelin, ganirelix, abarelix, cetrorelix, teverelix, octreotide, lanreotide, human growth hormone, interferon-alpha, interferon-beta, interferon-gamma, inter
  • the biologically active agent can be, for example, a simple organic compound, peptide, protein, DNA, or RNA material.
  • the biologically active agent can be in the form of a liquid or a finely divided solid that is either dissolved or dispersed in the liquid polymer/solvent composition.
  • the active agent is incorporated into the composition in an amount sufficient to achieve the desired therapeutic effect, the desired release profile, and the desired period of release of the active agent.
  • There is no critical upper limit on the amount of the active agent that is dispersed or dissolved in the liquid polymer/solvent solution as long as the solution has a fluid viscosity acceptable for injection through a small gauge syringe needle (e.g., gauge of 18-26).
  • the lower limit of the biologically active agent incorporated into the liquid polymer/solvent solution is dependent upon the activity of the active agent, the release rate needed to achieve the desired therapeutic level, and the length of time for treatment.
  • the biologically active agent is typically present in the composition at a range from about 0.2 percent to about 40 percent by weight relative to the total weight of the composition, and more preferably, at a range from about 1 percent to 15 percent by weight. Both soluble and insoluble biologically active agents can be incorporated into the liquid polymer/solvent system.
  • compositions can optionally include one or more adjuvants or additives, for example, biocompatible and nontoxic colorants, diluents, odorants, carriers, excipients, stabilizers, release rate modifiers, or the like.
  • adjuvants or additives for example, biocompatible and nontoxic colorants, diluents, odorants, carriers, excipients, stabilizers, release rate modifiers, or the like.
  • kits can include a container of a pharmaceutically-acceptable biodegradable liquid polymer, copolymer or terpolymer, a container of a biocompatible organic solvent that is dissolvable or dispersible in situ in a body fluid, and optionally at least one of a container of a therapeutically effective amount of a biologically active agent in a pharmaceutically-acceptable carrier or diluent, a syringe or other device for administering the liquid composition, and instructions or directions for preparation and administration of the compositions to form a polymeric implant.
  • an embodiment of a kit can contain a syringe of the liquid polymer/solvent composition and a separate syringe with the biologically active agent which can be coupled together for mixing the biologically agent within the liquid polymer/solvent composition prior to injection in the body.
  • Another embodiment of a kit can include a container or syringe of the liquid polymer/solvent/biologically active agent if the agent is stable in the liquid polymer solution.
  • a 250 mL, round-bottom single neck flask was dried with a blow dryer and flushed with nitrogen for several minutes. Then a glass T-joint was placed in the top of the flask, a nitrogen inlet was connected to the side of the T-joint, and the top of the T-joint was connected to rubber tubing which led to a glass pipette immersed in water. The nitrogen flow was set so as to provide a steady bubbling of nitrogen in the water.
  • the catalyst system was prepared by dissolving 0.2710 grams of Tin(II) 2-ethylhexanoate in 2 mL of toluene in a small vial. The vial was flushed with nitrogen and capped.
  • Example 1 The procedure in Example 1 was substantially repeated except that 13.6 mL of dodecanol and 0.1 mL of Tin catalyst were added to 72.1 grams of DL-lactide and 57.2 grams of caprolactone. The mixture was heated at 160° C. for 20 hours and the residual monomer removed under vacuum at 110° C. for 12 hours. A total of 123.1 grams of the viscous polymer was obtained after transfer to a sealed glass container. The fluid viscosity of this copolymer was lower than that of the copolymer obtained in Example 1 as evidenced by the amount of polymer that could be poured from the round-bottom flask into the sealed glass container. The color of this copolymer was also a little more yellow than that of the copolymer prepared in Example 1.
  • Example 1 The higher molecular weight and higher fluid viscosity copolymer obtained in Example 1 (23.1 grams) was weighed into a glass contained and 5.8 grams of N-methyl-2-pyrrolidone (NMP) was added to the liquid polymer. The mixture was heated with a blow dryer in efforts to completely dissolve the copolymer; however, the complete dissolution required stirring the contents with a spatula for about 15 minutes to obtain a solution with 80% w/w copolymer and 20% w/w NMP. The solution was still viscous, but definitely more flowable.
  • NMP N-methyl-2-pyrrolidone
  • Example 2 14.6 grams of the higher molecular and higher fluid viscosity copolymer obtained in Example 1 was weighed into a glass container and 9.6 grams of NMP were added to the liquid polymer. The mixture was then stirred with a spatula for several minutes to fully dissolve the polymer. The resultant solution with 60% w/w copolymer and 40% NMP was much less viscous than the solution obtained in Example 3.
  • Example 2 The lower molecular weight and lower fluid viscosity copolymer obtained in Example 2 (23.1 grams) was weighed into a glass container and 5.8 grams of NMP were added to the liquid copolymer. The mixture was then stirred with a spatula until the polymer was completely dissolved. The resultant solution with 80% w/w liquid copolymer and 20% w/w NMP had about the same flow viscosity as the 60/40 solution of the higher molecular weight copolymer described in Example 4.
  • Example 2 The lower molecular weight copolymer obtained in Example 2 (29.2 grams) was weighed into a glass container and 19.5 grams of NMP were added to the copolymer. The mixture was then stirred vigorously with a spatula until all of the copolymer had dissolved to give a solution with 60% w/w copolymer and 40% w/w NMP. This polymer solution was drawn up into a large plastic syringe and the desired amount of polymer solution was transferred to 1.2 mL male luer-lok gamma resistant polypropylene syringes using a stainless steel female coupler.
  • each syringe was capped with a female luer-lok polypropylene cap, and the syringes were placed in a bag for sterilization by exposure to gamma irradiation at 25 kGy.
  • Cisplatin powder was then weighed out in plastic trays at the desired amounts and the drug was transferred to female luer-lok polypropylene syringes with the plungers removed.
  • the plungers were re-inserted into the syringes, the syringes were held with the tips up, the caps were loosened, and the plunger tips with the cisplatin contents were moved up toward the tips until there was only a slight space between the drug and the tip of the syringe.
  • the caps were then tightened, and the syringes were set aside for labeling.
  • the doses and fill weights that were prepared are listed in Table 1.
  • Cisplatin Dose Fill Weights of Syringes 50 mg dose 760 mg liquid polymer solution 66 mg cisplatin 30 mg dose 529 mg liquid polymer solution 46 mg cisplatin 20 mg dose 414 mg liquid polymer solution 36 mg cisplatin 10 mg dose 299 mg liquid polymer solution 26 mg cisplatin
  • Example 6 The cisplatin/liquid polymer formulations described in Example 6 were evaluated in dogs with various forms of cancer. The specific dose of cisplatin administered in the liquid polymer formulation was determined by the weight of the dog being treated.
  • a syringe filled with the liquid polymer solution was coupled to the cisplatin dry powder syringe using the luer-lok system.
  • the contents of the liquid polymer solution were then passed into the cisplatin powder syringe by pressing on the plunger.
  • the mixture of cisplatin powder and liquid polymer solution was then moved back into the liquid polymer syringe, and this step was completed for about 50 back and forth times to complete the mixing of the cisplatin with the liquid polymer solution.
  • the homogenous mixture was then pulled back into the liquid polymer syringe, the two syringes decoupled, and a syringe needle attached to the liquid polymer syringe with the cisplatin/liquid polymer formulation.
  • the formulation was next injected intramuscularly into the animal at the desired dosage using a 20 gauge needle. Samples of blood from the treated animals were taken at baseline and after 1, 2, 3, and 4 weeks and analyzed for neutrophil levels as an indication of the release and activity of the cisplatin.
  • Cisplatin is an anti-cancer drug known to reduce neutrophil counts in dogs when administered intravenously as an aqueous solution.
  • Example 2 6.0 grams of the lower molecular weight copolymer described in Example 2 was dissolved in 6.0 grams of NMP to give a solution with 50% w/w copolymer and 50% w/w NMP. This solution was non-viscous and could be easily pulled up into a syringe using a 20 gauge needle. 5.0 grams of this liquid polymer solution was placed in a glass ampule and 50 milligrams of buprenorphine HCL powder from a weigh cup was placed in the ampule with the polymer solution to provide a formulation with approximately 1% w/w drug.
  • Buprenorphine is an opioid agonist-antagonist analgesic.
  • the mixture was stirred vigorously with a spatula until it appeared that the buprenorphine HCL powder had fully dissolved.
  • the polymer solution with the dissolved drug was then drawn up into a plastic syringe with a male luer-lok tip.
  • the plastic syringe with the polymer/drug solution was attached to the female luer-lok tip of a sterile filter from Advantec Mfgs., Inc.
  • the filter casing was polypropylene and the filter itself was hydrophobic Teflon with a pore size of 0.25 ⁇ m and a diameter of 25 mm.
  • the liquid polymer/drug solution was easily forced through the 0.25 ⁇ m filter to provide a clear and sterile liquid polymer/solvent/buprenorphine HCL formulation which was placed in an ampule with a rubber cap and stored. Analysis of the formulation by ultraviolet (UV) visible spectroscopy showed that the drug was present at a concentration of 0.98% w/w.
  • UV ultraviolet
  • each rat had its tail placed in a heated water bath to observe whether the animal felt the momentary discomfort from the heat and moved its tail in response to the heat stimulus. The length of time in seconds required for the rat to move its tail was recorded. If the animal did not move its tail within 10 seconds, the tail was removed from the water bath.
  • the three rats were used for each test group.
  • the three groups consisted of the liquid polymer/NMP solution without drug (vehicle control), the liquid polymer/NMP/buprenorphine HCL formulation at 0.6 mg dose of drug, and the liquid polymer/NMP/buprenorphine HCL formulation at 1.8 mg dose of drug.
  • Each of the vehicle control animals was injected in the scapular region with 180 ⁇ l of the liquid polymer/NMP solution using a 20 gauge needle.
  • the rats with a dose of 0.6 mg of drug were injected with 60 ⁇ L of the liquid polymer/drug solution, and the animals with a dose of 1.8 mg of drug were injected with 180 ⁇ L of the polymer/drug solution. All of the injections went well with no administration problems, no apparent implant bumps, and no apparent local tissue irritation effects.
  • Each animal was then tested for its response to the hot water stimulus at 4, 8, 24, 32, 40, 52, 60, and 72 hours. The results are given Table 3.
  • Example 2 10 grams of the lower molecular weight copolymer described in Example 2 was dissolved in 10.1 grams of NMP to give a solution with 50% w/w copolymer and 50% w/w NMP. To this solution was added 0.2085 grams of buprenorphine base. The white powdered base was thoroughly mixed and particles crushed until a clear solution was obtained. Then 0.4170 grams of palmitic acid was added to the polymer/drug/NMP solution to complex with the buprenorphine base to form buprenorphine palmitate. The white flaky palmitic acid was crushed and thoroughly mixed until a clear solution was obtained.
  • the resultant solution was then filtered through a 0.25 ⁇ m Teflon filter as described in Example 8 to produce a sterile solution with 1% w/w buprenorphine and 2% w/w palmitic acid.
  • the sterile solution was stored in a glass ampule with a rubber cap until needed.
  • Example 8 Samples of the buprenorphine HCL/liquid polymer formulation described in Example 8 and the buprenorphine base/liquid polymer formulation described in Example 11 were evaluated in dogs for in vivo release of the drug.
  • the Buprenex® control formulation was administered to the dogs subcutaneously every 8 hours at a dose of 0.03 mg/kg for 64 hours (nine administrations) to give a total dose of 0.27 mg/kg.
  • the two liquid polymer formulations were administered only once at a total dose of 0.27 mg/kg to match the dose given with the Buprenex® control.
  • the plasma levels with the Buprenex® control formulation were more erratic due to the administration every 8 hours. Based upon the plasma levels obtained with the liquid polymer formulations, it appears that they will provide with only one administration the same degree of pain control as the Buprenex® control with eight administrations, and they will do this without any burst effects from the polymer system.
  • the 60/40 liquid polymer solution described in Example 4 was used to fill a 1.2 cc polypropylene syringe with male luer-lok fittings to about 0.5 cc of polymer solution. Also, a small amount of the nonpolymeric material, palmitic acid, was added to a container with some of the 60/40 liquid polymer solution to give a solution containing by weight 54% liquid polymer, 36% NMP, and 10% palmitic acid. About 0.5 cc of this solution was filled into a 1.2 cc polypropylene syringe with a male luer-lok fitting.
  • Example 2 a small amount of the higher viscosity liquid polymer described in Example 1 was dissolved in triacetin, a more lipophilic solvent, at 50% w/w polymer and 50% w/w triacetin. About 0.5 cc of this liquid polymer solution was also filled into a polypropylene syringe.
  • Each of the syringes with the liquid polymer solutions were connected to a female luer-lok polypropylene syringe containing 50 mg of doxycycline hyclate powder, and the contents of the syringe moved back and forth between the two syringes 50 times.
  • Doxycycline is a broad-spectrum tetracycline antibiotic.
  • a control sample of the solid polymer, poly(DL-lactide) dissolved in NMP at a ratio of 37% w/w polymer to 63% w/w NMP was also mixed with 50 mg of doxycycline hyclate for 50 times.
  • the thoroughly mixed formulations were then drawn back into the male syringe, the two syringes decoupled, and the contents of the syringes injected without a needle into small containers with 10 mL of water.
  • each of the formulations before injection into the water was yellow due to the color of the doxycycline, and the release of the drug could be easily followed by observing the color of the water receiving fluid.
  • the solid polymer/doxycycline formulation gave a solid intact mass immediately upon insertion into the water receiving fluid. All of the liquid polymer/doxycycline formulations gave liquid films upon insertion into the water receiving fluids.
  • Both the 60/40 liquid polymer/NMP and the 54/36/10 liquid polymer/NMP/palmitic acid formulations gave liquid films upon the top of the water whereas the liquid polymer/triacetin formulation formed a liquid film at the bottom of the water container. With time, the liquid polymer/palmitic acid formulation tended to thicken whereas the other liquid polymer formulations remained fluid liquids.
  • the solid polymer formulation had released more drug than the other formulations.
  • the amount of drug release was in the order of the solid polymer/NMP>50/50 liquid polymer/triacetin>60/40 liquid polymer/NMP>54/36/10 liquid polymer/NMP/palmitic acid.
  • the order of drug release was solid polymer/NMP>50/50 liquid polymer/triacetin>54/36/10 liquid polymer/NMP/palmitic acid>60/40 liquid polymer/NMP.
  • the 60/40 liquid polymer/NMP and the 54/36/10 liquid polymer/NMP/palmitic acid still had some yellow color in the liquid implant whereas the solid polymer/NMP implant was white.

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US12/100,562 US20090181068A1 (en) 2008-01-14 2008-04-10 Low Viscosity Liquid Polymeric Delivery System
EP11005377A EP2371400A3 (de) 2008-01-14 2009-01-13 System zur Abgabe von Flüssigpolymer mit niedriger Viskosität
CA2714757A CA2714757C (en) 2008-01-14 2009-01-13 Low viscosity liquid polymeric delivery system
PT09702328T PT2244752E (pt) 2008-01-14 2009-01-13 Sistema de distribuição polimérico líquido de baixa viscosidade
AT09702328T ATE526046T1 (de) 2008-01-14 2009-01-13 Niederviskos-flüssigpolymer-zuführungssystem
PL09702328T PL2244752T3 (pl) 2008-01-14 2009-01-13 Układ dostarczania z ciekłego polimeru o małej lepkości
PCT/US2009/030853 WO2009091737A2 (en) 2008-01-14 2009-01-13 Low viscosity liquid polymeric delivery system
CA2787097A CA2787097C (en) 2008-01-14 2009-01-13 Low viscosity liquid polymeric delivery system
EP09702328A EP2244752B1 (de) 2008-01-14 2009-01-13 Niederviskos-flüssigpolymer-zuführungssystem
SI200930120T SI2244752T1 (sl) 2008-01-14 2009-01-13 Nizkoviskozni tekoči polimerni dovajalni sistem
US12/812,670 US8187640B2 (en) 2008-01-14 2009-01-13 Low viscosity liquid polymeric delivery system
ES09702328T ES2370377T3 (es) 2008-01-14 2009-01-13 Sistema de administración de un líquido polimérico de baja viscosidad.
HK11104383.4A HK1150982A1 (en) 2008-01-14 2011-05-03 Low viscosity liquid polymeric delivery system
CY20111101262T CY1113604T1 (el) 2008-01-14 2011-12-20 Συστημα παροχης υγρου πολυμερους χαμηλου ιξωδους
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