Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—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
  • 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
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/40—Cyclodextrins; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to a formulation administered parenterally to a subject.
• the invention relates to a particulate formulation, which, on administration to a subject such as an animal, forms a depot.
• the agent has a variety of effects including, for example, releasing an antibiotic into the subject's bloodstream.
• Typical methods of administration of such agents are often tablets, capsules, injections and other such methods.
• a method also employed is the use of an implant containing an active ingredient.
• Implants are particularly advantageous as the active agent can be released over a time period whereas other treatments such as tablets breakdown rapidly once administered to the subject.
• implants are a desirable means of treating an animal as the treatment need only be applied once and the animal is then treated on a progressive basis without further intervention by the vet or animal handler.
• a typical implant is often a device which is either expelled from the animal once administration has completed or the implant breaks down in the animal and is expelled during normal bodily functions.
• implant device has obvious advantages as described above, they also have problems with regard to the method of administration and the type of materials used. Some implant devices do not breakdown and are either removed surgically or not removed at all. This can cause problems to the subject such as leaching of toxic materials from the implant, a physical lump or obstruction in the body of the subject, and in the case of farm animals, solid objects on which machinery used for processing the animal can become caught or damaged by.
• an implant that is a biocompatible material to the subject and which can break down within the subject.
• Implants being solid or semi-solid devices, are difficult to administer to internal regions of the subject.
• the devices have traditionally been administered either orally, physically inserted into a body cavity, or inserted surgically.
• Oral and physical insertion limits the location of the device to the oral passage and/or body cavities. Surgery can insert these devices into areas oral and physical methods cannot reach, however this method is traumatic for the subject, expensive and time consuming. As a result it is only warranted in extreme circumstances.
• injection formulations need to be of low to moderate viscosity in order to operate the injection device e.g. plunge the syringe. Implants thus cannot be administered via injection due to the solid / semi-solid nature of the device.
• the solvent carrier disperses into the subject leaving the implant material behind.
• a problem is that the solvents employed in these methods have needed to be aggressive in order to dissolve the implant material. Aggressive solvents then become a part of the problem as the subject is injected with potentially toxic materials that may cause further illness or ailment.
• thermo-reversible gels solidify in warm conditions - opposite to standard gels which solidify on cooling.
• the gel solidifies in the subject (assuming the subject is warm blooded) and hence the implant forms.
• a typical example is described in U.S. Pat. No. 5,702,717 to Cha et al.
• the above prior art relates to use in humans and animals, particularly livestock.
• An alternative for depot use is in plants, especially woody plants.
• treatment of trees is done via the roots e.g. liquid fertilisers.
• One technique used for treatment of fungus disease in a tree is to insert an impregnated dowel into the tree trunk itself.
• the dowel is impregnated with fungicide which is taken up by the sap of the tree.
• This method involves damage to the tree i.e. the drilling of a hole.
• the active agent is only able to be applied to the outside of the dowel and is essentially a one off release i.e. there is no sustained release of active which can be required to treat certain plant diseases.
• a formulation for parenteral administration to a subject including: at least one water miscible solvent; at least one gelling agent; at least one active agent; characterised in that the gelling agent is in particulate form and suspended in the solvent.
• a formulation as described above wherein, when the formulation is administered to a subject, a depot forms which contains the active agent. Preferably, this agent is then released from the depot on a sustained basis.
• the sustained basis is selected from: over a time period of days; a steady rate of release; and combinations thereof.
• composition of the present invention is such that on entry into the subject, the solvent disperses and the gelling agent coagulates to form a depot within the subject and from which the active agent is released on a sustained basis.
• the formulation of the gelling agent at least physically contains the active agent from dissolution into the subject on initial administration.
• the formulation is administered parenterally, where, for the purposes of this specification, 'parenterally' is defined as by injection via a route selected from the group consisting of: subcutaneous; intramuscular; intraorbital; intracapsular; intraspinal; intrasternal; intravenous; within a plant; and other such known routes. More preferably the route used is selected from the group consisting of: subcutaneous; intramuscular; and combinations thereof.
• the subject to which this formulation can be applied includes animals, (including humans) and plants.
• the preferred embodiment is for administration to an animal.
• the animals are livestock selected from the group consisting of: cattle; sheep; deer.
• This type of animal is preferred as the high value of the animal justifies the cost of the treatment.
• it is both undesirable from a cost point of view and often difficult to administer a number or treatments to livestock as they may often be in remote locations and distressed by such treatments.
• a preferable group of plants to which this formulation may be used is woody plants. Most preferably, the plants are trees.
• a fungicide is used as the active agent and the formulation is injected into the tree, for example into a small hole drilled into the tree.
• the aqueous environment inside the tree e.g. sap
• other plant active agents may also be used in this application.
• a water miscible solvent is defined as a liquid that is susceptible of being dissolved in, or mixing with, water. This is important in order to ensure that the solvent used does not linger in the subject and cause possible side effects.
• a useful point of the invention is that often, water miscible solvents are less aggressive solvents and hence more physiologically acceptable.
• the solvent is selected from the group consisting of: ethanol; glycerin; polyethylene glycol, propylene glycol and combinations thereof.
• the gelling agent forms a gel or semi-solid on dispersal of the solvent.
• 'gel or semi- solid' is defined as a viscous or solid like material formed by the aid of a suitable gelling agent.
• Such gels have a moderate to high viscosity - that is they do not pour freely.
• gel materials are selected from the group consisting of: cyclodextrins; polyethylene oxide; hydroxypropyl methylcellulose; polyvinyl alcohol; polyvinyl pyrrolidone; methylcellulose; ethylcellulose; hydroxyethyl cellulose; sodium carboxymethyl cellulose; dextran; gelatine; pectin; sodium poly(acrylic acid); carboxymethyl cellulose and combinations thereof.
• gels are preferred due to their pharmaceutical and physiological acceptability and ability to form gels of desirable viscosity for use in such depot formation.
• the preferred formulation includes 5 to 15% w/w polyethylene oxide, 10 to 50% w/w ethanol, 30 to 90% w/w glycerin and active agent quantities as required for the application.
• the formulation can be used with any active agent.
• the agent may have biological activity, chemical activity, physical activity, and combinations thereof. Most preferably the agent is biologically active.
• Typical agents include those selected from the group consisting of: antibacterial agent; antifungal agent; anti-inflammatory agent; antiparasitic agent; anti- neoplastic agent; analgesic agent; anaesthetic agent; antipsychotic agent; vaccine; central nervous system agent; growth factor; hormone; antihistamine; osteoinductive agent; cardiovascular agent; anti-ulcer agent; bronchodilating agent; vasodilating agent; birth control agent; antihypertensive agent; anticoagulant; antispasmodic agent; fertility-enhancing agent; and combinations thereof.
• agents are preferably fungicides.
• the active agent is in the form of a solid, a liquid or combinations thereof e.g. a solid suspended in a liquid.
• the agent is dispersed in either: the gelling agent; the solvent; and combinations thereof.
• a plurality of agents may be used and may be incorporated entirely within the gelling agent, the solvent or a mixture in both the solvent and gelling agent.
• the agent is evenly distributed within the solvent and/or gelling agent.
• the gelling agent is distributed evenly throughout the solvent as a particulate suspension. This has the advantage of even dispersion when injected into the subject.
• Particulates are of a size range from 1 nm to 5mm in diameter. More preferably the diameter is from 1 nm to 0.1mm in diameter.
• the suspension remains largely stable (biologically, chemically and physically) when stored. Settling can occur. Simple shaking of the formulation e.g. by hand, will re-establish the desired particulate suspension.
• the solvent disperses naturally into the subject fluids. This is a result of the water miscible solvent being introduced to an aqueous environment e.g. an animal's body. For example, in the case of an animal, the solvent dissolves into the animal's blood stream.
• the solvent being water miscible, easily dissolves into such environments without leaving harmful residue levels.
• the gelling agent particles coagulate to form a depot.
• 'coagulation' is defined as the dissolution of a particulate material into a gelatinous mass which may also be called clotting, clumping or combining.
• the depot formed traps the active agent within the depot in a relatively short period of time such that any free active agent (e.g. agent in the solvent solution) is substantially captured by the coagulating process before being carried away from the depot.
• any free active agent e.g. agent in the solvent solution
• 'depot' is defined as a substance (preferably containing an active agent) that is retained in close proximity to the site of injection so that release of the active agent occurs over a prolonged period of time.
• the depot formed is of a consistency selected from the group consisting of: a viscous material; a gel or semi-solid; and combinations thereof.
• the depot remains subcutaneous if the depot is administered subcutaneous or intramuscular if the depot is administered intramuscular.
• the depot formed is water soluble. It is understood by the applicant that the depot erodes / dissolves in the solution environment of the subject over time and in doing so releases the active agent into the subject.
• dissolution of the depot occurs over a sustained and/or regular length of time.
• Typical rates of release are dependent on the active agent desired dosage.
• the rate of release varies according to factors selected from the group consisting of: initial particle size; levels of gel in the formulation; the amount and type of active agent; levels of any additional materials in the formulation; the subject; subject metabolism; the administration site; and combinations thereof.
• the ingredients used are pharmaceutically and physiologically acceptable.
• other pharmaceutically and physiologically acceptable agents can be included that are substantially inert with respect to the active agent or agents and mechanisms of the formulation as described above.
• a further advantage of the present invention is that leakage from the injection site is minimised or removed altogether.
• the gelling characteristics of the formulation bind the active agent within close proximity of the injection site. This avoids back flow of formulation out through the injection point thus stopping unwanted waste of agent and also gives a clean wound/administration area.
• a method of treatment of a subject requiring such treatment by parenteral administration of a formulation to a subject, wherein the formulation includes: at least one water miscible solvent; at least one gelling agent; at least one active agent; characterised in that the gelling agent is in particulate form and suspended in the solvent.
• a formulation for treatment of a subject requiring such treatment by parenteral administration of a formulation to a subject, wherein the formulation includes: at least one water miscible solvent; at least one gelling agent; at least one active agent; characterised in that the gelling agent is in particulate form and suspended in the solvent.
• the present invention uses pharmaceutically and physiologically acceptable materials that can be easily injected whilst still providing an implant for sustained release of an active agent.
• the depot formulation of the present invention it is easier to dose the subject as only one injection is required rather than the difficulties of surgery or a series of treatments associated with tablets or liquids.
• the formulation uses compounds that are biologically 'friendly', harmful residues are avoided such as those from aggressive solvents.
• Figure 1 shows the exterior of a portion of excised deer muscle tissue comparing a control sample against that of the present invention
• Figure 2 shows the interior of a portion of excised deer muscle tissue comparing a control sample against that of the present invention
• Figure 3 shows the interior of a portion of teat cistern of excise bovine mammary gland showing the result from an infusion of formulation of the present invention.
• the invention relates to a formulation consisting of a gelling agent or agents, a water miscible solvent or solvents and an active agent or agents.
• the aim of the suspension is to deliver active agent or agents to a subject in the form of a depot that, on parenteral administration to the subject, forms a depot.
• the depot will disperse in time and during this time period, active agent or agents are released into the subject.
• the following examples illustrate the gel forming characteristics of the formulation.
• the nature of the depot i.e. viscous solution, gel or semi-solid is described by addition of gelling agent to solvent to show that the effect of selection of depot formation material on the final depot characteristics. Results are shown in Table 1 below.
• Example 1 the experiment in Example 1 is repeated using polyethylene oxide as the gelling agent and ethanol as the solvent.
• a formulation of the present invention is used with polyethylene oxide used as the gelling agent and a combination of ethanol and glycerin as the solvents.
• Sodium fluoresceine is used as a dye to show experimental results.
• a control sample is used for comparison which includes no gelling agent (only glycerin, ethanol and sodium fluoresceine).
• composition of each formulation is as shown in Table 2 below.
• test and control formulations are shown.
• the injection point of the test formulation (1) shows very little leakage of the formulation via the needle tract.
• the control formulation shows extensive leakage (2) via the needle tract (3).
• the invention formulation generally indicated by arrow (9) has gelled and adhered to the internal teat cistern wall (10).

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Inorganic Chemistry (AREA)
• Oncology (AREA)
• Dermatology (AREA)
• Communicable Diseases (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Tropical Medicine & Parasitology (AREA)
• Neurosurgery (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Medicinal Preparation (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (2)

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Family Applications (1)

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• 2002
  • 2002-05-16 NZ NZ51899702A patent/NZ518997A/xx not_active IP Right Cessation
• 2003
  • 2003-05-16 CA CA002486133A patent/CA2486133A1/en not_active Abandoned
  • 2003-05-16 WO PCT/NZ2003/000095 patent/WO2003097009A1/en not_active Ceased
  • 2003-05-16 AU AU2003228174A patent/AU2003228174A1/en not_active Abandoned
  • 2003-05-16 JP JP2004505008A patent/JP2005538052A/ja active Pending
  • 2003-05-16 EP EP03725918A patent/EP1549291A4/de not_active Withdrawn

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