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WO2003011214A2 - Nouvelles methodes et formulations concues pour administrer des agents actifs - Google Patents

Nouvelles methodes et formulations concues pour administrer des agents actifs Download PDF

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Publication number
WO2003011214A2
WO2003011214A2 PCT/US2002/021646 US0221646W WO03011214A2 WO 2003011214 A2 WO2003011214 A2 WO 2003011214A2 US 0221646 W US0221646 W US 0221646W WO 03011214 A2 WO03011214 A2 WO 03011214A2
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Prior art keywords
composition
medicinal
group
sulfate
matrix
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PCT/US2002/021646
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English (en)
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WO2003011214A3 (fr
Inventor
Garfield P. Royer
Joseph A. Manda
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Royer Biomedical, Inc.
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Priority to AU2002322424A priority Critical patent/AU2002322424A1/en
Publication of WO2003011214A2 publication Critical patent/WO2003011214A2/fr
Publication of WO2003011214A3 publication Critical patent/WO2003011214A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • 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
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0063—Periodont
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin

Definitions

  • the subject invention relates to novel compositions and methods for delivery of active agents.
  • Polymer matrices designed for controlled release of bioactive compounds can be non- resorbable or resorbable.
  • resorbable means degradable in the body by erosion from the surface or breakdown from within.
  • the mechanism can involve either a chemical reaction, such as hydrolysis, or dissolution.
  • Non-resorbable polymers such as polymethylmethacrylate
  • These materials suffer from the disadvantage that they must be retrieved, which involves a second intervention and entails the risk of infection (HW Bucholz, et al., (1970) Chiburg, 43 , 446).
  • Resorbable polymer matrices for controlled release are usually based on an oxygenated monomer, which is condensed in organic solvent to yield the polymeric product.
  • the bioactive agent and the polymer are then combined in such a way as to give a timed-release formulation.
  • the combination of active ingredient and polymer often involves organic solvents as well.
  • the use of organic solvents is a decided disadvantage, especially when large-scale production is required. Toxic residues of organic solvents are a concern. Proteins and many polypeptides are incompatible with organic solvents.
  • the types of polymers in this category include:
  • Naturally occurring proteins may be used as structural components in drug-delivery matrices (Royer, US Patent 4,349,530; Royer, US Patent 5,783,214; Lee, Science (1981) 233-235).
  • One deficiency of proteinaceous delivery matrices is that they can exhibit instability especially in environments where an inflammatory reaction is present such as a site of localized sepsis.
  • WO 99/15150 discloses a stable, yet practical composition for use in inflamed sites comprising an inorganic compound, a matrix polymer and/or a complexing agent.
  • This composition has the advantage of being biocompatible but, unlike synthetic organic polymers, no non-aqueous solvents are required in the preparation.
  • the drug is incorporated as a solid or as part of the matrix polymer solution.
  • the material can also be used as a cement, that is, it can be injected directly into a lesion and allowed to solidify in situ.
  • ivermectin is an antiparasitic which has been formulated in liquid and paste form.
  • the liquid consists of surfactants that form micelles in which the insoluble ivermectin molecule is isolated from and dispersed in water. Liquids can be injected which is inconvenient and has accompanying risks such as infection and irritation at the injection site. Further, horse owners are often averse to giving intra-muscular or subcutaneous injections.
  • the liquid can be drenched which means squirted into the back of the horses mouth or by "tubing," i.e., naso-gastric intubation, generally a procedure reserved for veterinarians.
  • tubing i.e., naso-gastric intubation
  • the paste formulation of ivermectin is also injected into the back of the horse's mouth.
  • Horse owners and veterinarians are sometimes required to restrain the horse with a twitch or other device in order to use the paste reliably.
  • a halter is required in the vast majority of horses. All of the above aforementioned procedures require restraint of the horse.
  • the recommended regimen for ivermectin is once every 6-8 weeks.
  • the deworming is accomplished either by the horse owner, by stable workers, or in rare cases by a veterinarian. Because of the inconvenience of using paste dewormers, owner compliance can be a problem. The second problem involves inaccurate dosing. In the process of injecting the paste into the horse's mouth, the horse will throw its head and discharge some of the paste or refuse to swallow. The user of the paste syringe is then required to make a decision as to how much was lost.
  • Ivermectin is a semi-synthetic derivative of abamectin. It typically contains at least 80% of 22,23 dihydroavemiectin Bla and 20% of 22,23 -dihydroavermectin Bib.
  • the term "ivermectin” includes the various formulations used by those skilled in the art. Ivermectin is lipophilic with very low water solubility (4mcg ml). As expected, ivermectin strongly binds to serum proteins. With a molecular weight of 875 and 20 chiral centers, it is a large complex structure containing a lactone macrocycle along with two gycosidic linkages. The compound is epimerized by base and UV light (see Ivermectin and Abamectin (1989) WC Campbell, Ed., Springer- Verlag, NY).
  • ivermectin as an antiparasitic is attractive in that it acts by disruption of gamma-aminobutyric acid mediated neurotransmission in parasites such as nematodes and arthropods but does not affect mammals. Higher organisms have receptors for gamma- aminobutyric acid but only in the CNS, not penetrable by ivermectin.
  • the spectrum of ivermectin is quite broad and includes virtually all parasites that infect horses except tapeworms and hookworms, which are relatively uncommon. Fortunately, ivermectin- resistant strains of equine parasites have not evolved.
  • ivermectin Two other very attractive features of ivermectin include a high margin of safety and the requirement of very low dosages. Cattle were treated with 30 times the recommended dose with little or no toxicity. The dosage in the horse and other livestock is 200 mcg/kg. The recommended frequency of dosing for horses is once every 6-8 weeks. Domestic animal (egs. cats and dogs) use of ivermectin is for the prevention of canine and feline heartworm disease (Dirofilaria immitis) and for the treatment of intestinal hookworms, roundworms, and whipworms.
  • Canine and feline heartworm disease Dirofilaria immitis
  • Administration typically entails dosing the ivermectin to the cats and dogs on a once a month regime at a minimum of 6.0 meg per kilogram of body weight (2.72 mcg/lb).
  • the current dosage forms available for ivermectin include both an extruded meat-by-product and a compressed chewable tablet. In both cases, the palatability of the product is poor.
  • the subject invention relates to a delivery matrix formed by mixing: an inorganic compound capable of undergoing hydration and/or crystallization, plus, a conditioning agent which improves stability, extends the residence time, and provides for control of the release profile, and optionally, a matrix polymer, and/or a complexing agent.
  • the subject invention also relates to a feed composition
  • a feed composition comprising: a) feed, b) a solid composition comprising an active agent dispersed throughout a solid matrix hydration reaction product of an aqueous mixture comprising said active agent, an inorganic compound capable of undergoing hydration, a conditioning agent, and/or a matrix polymer, and/or a complexing agent, and uses thereof.
  • the subject invention relates to compositions and methods for delivery of active agents. Safety, convenience, and reliability of dosing are advantages of the instant invention over other dosage forms.
  • the inorganic compound-conditioning agent composites described herein are resorbable by dissolution. No acid is produced as opposed to hydrolytic erosion of polymer matrices such as polyesters.
  • the inorganic-conditioning agent composite described herein requires no organic solvent in matrix preparation or drug loading. No acid is produced on erosion so it is useful for orthopedic applications.
  • the inclusion of the conditioning agent and advantageously the matrix polymer imparts control over the release profile of the active ingredient and distinguishes this material from unadulterated plaster of Paris which is rigid and safe but is otherwise lacking in performance (D Mackey, et al. (1982) Clin. Orthop. 167, 263; GW Bowler, et. al. (1994) J. Trauma, 36, 331).
  • the matrix described in commonly-owned WO 99/15150 may also contain a complexing agent to retard the release of the active ingredient.
  • the matrix formulation of this invention contains improved hydrophobic complexing agents, e.g., pamoates, and conditioning agents that can serve as water repellants. Water repulsion of these matrices allows for set-up in an aqueous environment. In fact, when a conditioning agent is present, the matrix will solidify when totally submerged. This trait is important when the material is used in orthopedic or dental applications. Examples include filling of periodontal defects or treating an osteomyelitic lesion. Also, the lifetime in the environment, or the body, is extended. This extended residence time is important in the delivery profile. Multiple formulations with different residence times can be combined. The resultant release profile has a desirable form and resembles zero-order. When hydrophobic complexing agents and conditioning agents are used with hydrophobic medicinal agents, the release profiles can be controlled.
  • hydrophobic complexing agents and conditioning agents are used with hydrophobic medicinal agents, the release profiles can be controlled.
  • Entrapment of active substances within the resorbable biocompatible matrix described herein yields a delivery system, which permits controlled and localized release of a bioactive agent.
  • Inorganic compounds such as CaSO4-l/2 H2O (calcium sulfate hemihydrate) can be combined with a polymer in the presence of a bioactive agent to produce a solid which constitutes a biocompatible and resorbable delivery matrix (See WO 99/15150 — the entire contents of which is incorporated by reference herein).
  • the matrix polymer increases the internal viscosity of the device, which slows the efflux of the bioactive agent.
  • the delivery system is formed by mixing:
  • the resulting composition can then be added to food or feed.
  • the active agent is mixed with one of the inorganic compound, conditioning agent, matrix polymer and complexing agent, prior to mixing with food or feed.
  • a conditioning agent such as calcium stearate provides improved stability and added control of the release profile and residence time. Water repulsion can also stabilize the solid dosage form with extension of residence time.
  • Calcium stearate is included at a rate of up to 30 % w/w, advantageously 2.5-20% w/w, based on the amount of inorganic compound, e.g., calcium sulfate hemihydrate. Even higher levels of calcium stearate are obtainable depending on the nature and amounts of other components.
  • the nature and amount of matrix polymer, the relative proportions of calcium sulfate hemihydrate and matrix polymer (liquid), the complexing agent, and the nature and amount of the conditioning agent permit the adjustment of the release profile and residence time of the matrix.
  • the matrix biopolymer can serve as a solubilizing agent.
  • the polymer can bind the active ingredient and carry it to the intestinal mucosa for absorption and uptake into the bloodstream.
  • the matrix polymer can also act to stabilize the active ingredient.
  • Calcium sulfate I/2H2O (hemihydrate) (hh) is the preferred inorganic component.
  • the hemihydrate takes up water and crystallizes as the higher hydrate.
  • Unadulterated calcium sulfate matrix exhibits poor drug release profiles. With conditioning agents, and optionally matrix polymers and complexing agent-active agent complexes the release profiles are improved.
  • Other inorganics can be employed such as calcium silicates, aluminates, hydroxides and/or phosphates (see pages 72, 95, 327 in Reference Book of Inorganic Chemistry (1951) Latimer, W.H., and Hildebrand, J.M., Macmillan, New York, hereby incorporated by reference in its entirety).
  • Conditioning agents are used to slow the erosion rate and permit solidification in the presence of moisture (repels water). All conditioning agents have a hydrophobic moiety.
  • Calcium stearate is an advantageous choice for a conditioning agent that meets the criteria of safety and efficacy.
  • Other calcium salts are useful in this regard. Examples include saturated and unsaturated carboxylic acids, aromatic carboxylic acids, corresponding phosphates, phosphonates, sulfates, sulfonates, and other compounds containing a hydrophobic moiety with a negatively charged anion. Salts of undecylenic acid are useful, in that they provide stability and also antifungal action.
  • the use of calcium as the cation is advantageous but other cations will suffice; the group includes, but is not limited to, zinc, magnesium, aluminum and manganese.
  • the generalized chemical structure can be illustrated as follows:
  • R-X-M where R is alkyl, alkenyl, alkynyl or aryl, where X is a carboxylate, a carboxylic acid, an aromatic carboxylic acid, a corresponding phosphate, a phosphonate, a sulfate, or a sulfonate, and where M is a metal ion such as calcium, zinc, magnesium, aluminum or manganese.
  • M is the metal ion Ca2+- Cationic conditioning agents can also be employed, i.e.,
  • the preferred matrix polymers for medical use are biocompatible (non-toxic, non-allergenic, non-immunogenic) water soluble compatible with other components in the formulation
  • matrix polymers examples include chondroitin sulfate, dextran (1-50%), hyaluronic acid (e.g., 1-5%), dextran sulfate, DEAE -dextran, pentosan polysulfate, polyethylene glycol, polyvinylpyrrolidone, proteins such as collagen (gelatin) and fibrinogen and polypeptides.
  • a crosslinkmg agent is added to the matrix polymer. The addition of the crosslinkmg agent causes a reaction which leads to a higher molecular weight matrix polymer which increases viscosity. Diffusion is thereby inhibited. See Royer U.S. Patent No. 5,783,214 hereby incorporated by reference in its entirety. Counterions, are advantageously sodium or calcium. Chitosan as well as cationic polypeptides, polylysine, and polyarginine are examples of useful polymers that are positively charged at neutral pH.
  • the function of the matrix polymer is to control the viscosity, which is dependent on the nature, molecular weight and concentration of the polymer.
  • the rationale for using polymers and polymeric complexing agents is based on Stokes law:
  • Complexing agents can be polymers or small molecules. The agents can form ionic bridges or hydrophobic bonds with the molecule to be delivered. The complexes involving the bioactive agents can range from sparingly soluble to soluble. Disodium pamoate is a good example of a complexing agent that forms sparingly soluble adducts with cationic bioactive ingredients. Disodium methylene disalicylate is a similar molecule to disodium pamoate that performs the same function. Procaine and benzathin can be used to reduce the solubility and rate of efflux of anionic bioactive agents. Additional complexing agents are presented in WO 99/15150.
  • Medicinals both non-protein drugs and medicinal proteins
  • Therapeutics, antigens, antibodies, adjuvants, and regulatory molecules such as hormones exemplify bioactive agents that are useful.
  • the matrix prepared as described above can be combined with soluble bioactive agent and optionally a complexed bioactive agent, to provide an initial burst and intermediate control.
  • Clindamycin-HCl free in solution, plus clindamycin-pamoate (as a sparingly soluble salt complex), plus clindamycin-pamoate encapsulated as above in the calcium sulfate- conditioning agent-polymer matrix comprise a three component system for delivery of clindamycin with a desirable release profile.
  • This combination has been employed to provide an antibiotic depot in cats and dogs.
  • a depot can be formed of the soluble drug and the complexed drug alone.
  • Another embodiment of the invention is a formulation containing a mixture of Drug calcium sulfate, Drug calcium sulfate-calcium stearate 2.5%, Drug calcium sulfate-calcium stearate 5.0% and Drug calcium sulfate-calcium stearate 10%.
  • Antibiotic formulations can be used to treat localized infections such as osteomyelitis, joint infections, and diabetic foot ulcers. Subsequent to surgical debridement (drainage), beads (e.g., 3mm), microbeads, or cement is installed at the site of the infection. Infected screw channels in bones can be treated successfully using amikacin cement. Microbeads containing amikacin pamoate are effective in the treatment of joint sepsis. For dead space management following surgical repair of fractures, antibiotic cement can be used. Another use of antibiotic matrix involves dentistry. Periapical abscesses can be treated with microbeads containing amikacin/clindamycin. Doxycycline cement can be administered by syringe to fill periodontal defects (See Example 16).
  • anti-infectives useful in conjunction with the formulations of the invention include gentamicin, clarithromycin, doxycycline minocycline and lincomycin, amikacin, penicillin, cefazolin, ciprofloxacin, enrofloxacin, norfloxacin, silver sulfadiazine, imipenem, piperacillin, nafcillin, cephalexin, cefoperazone, vancomycin, tobramycin, nystatin, and amphotericin B or salts thereof (e.g., pamoate salt).
  • Forming the pamoate (a complexing agent) of anti-infectives to form complexes such as amikacin pamoate, clindamycin and gentamicin pamoate, are useful alone or in the formulations of the invention.
  • Cis- platin, and other anti-neoplastic agents can be delivered locally with beads (e.g., 3mm) or with microbeads prepared as described herein. In one embodiment, localized administration is beneficial in that systemic toxicity is eliminated but concentrations in the area of cancerous tissue are high.
  • Vaccine antigens can be delivered with the system of the invention, for example, with microbeads (i.m. injection). The system of the invention can also be used for formulation of nucleic acid vaccines.
  • Antiparasitics such as macrocyclic lactones can be delivered using the delivery system of the invention.
  • Ivermectin has been formulated in a micro-granular form as described in detail below. Briefly, ivermectin is finely ground and blended with calcium sulfate hemihydrate. Calcium stearate is included to the extent of 5-10% (w/w) of the calcium sulfate hemihydrate. A solution of a pharmacologically acceptable polymer such as polyethyleneglycol is added to the mixture of powders. The calcium sulfate hemihydrate dissolves and is converted to calcium sulfate dihydrate, which crystallizes; the ensuing solid mass is allowed to dry at room temperature. Milling and seizing yields the dosage form.
  • a pharmacologically acceptable polymer such as polyethyleneglycol
  • Moxidectin can also be used.
  • various orally active anti-infectives useful in conjunction with the formulations of the invention include lincomycin, penicillin, ciprofloxacin, enrofloxacin, norfloxacin, nafcillin, cephalexin, orally active cephalosporin.
  • All animal health vitamins can be included in the delivery system for administration to animals.
  • Examples include: vitamin C, vitamins A and D, vitamin B12, and equine hoof growth supplements.
  • Animal health minerals can be included in the feed compositions of the invention. Examples are copper sulfate, organic iodide, potassium, etc.
  • the delivery system of the invention can also be used to deliver non-medical bioactive agents include sterilants, pheromones, fungicides, algicides, growth regulators, nutraceuticals, repellents, and nutrients. (See also WO 99/15150). * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
  • the amount of calcium sulfate hemihydrate is set at about lg
  • the amount of bioactive substance is set in the range of l-300mg.
  • the concentration of polymer can be 10, 20, 30, 40, as high as 50 % (w/v).
  • the conditioning agent is present in the range of 5-30% (w/w) based on calcium sulfate.
  • the ratio of liquid/solid is 0.4-0.8, preferably 0.6.
  • the calcium sulfate hemihydrate can be sterilized by dry heat (e.g. 140 for 4hr); the polymer solution is sterilizable by filtration (0.2-micron filter). Terminal sterilization by gamma irradiation at 15-18 kGy is also effective.
  • the production of the delivery system can be illustrated as follows:
  • a conditioning agent such as calcium stearate can be pre-mixed with the calcium sulfate hemihydrate.
  • the slurry can be injected into the desired location with solidification in situ.
  • This composition is ideal for dental and orthopedic applications.
  • the fact that the slurry can set-up in the presence of moisture is very advantageous.
  • a delivery system can be produced by: blending of an inorganic substance such as calcium sulfate hemihydrate and optionally a conditioning agent such as calcium stearate, both in powder form, mixing with matrix polymer solution (the active agent can be dissolved or suspended in the polymer solution or the solid drug can be finely ground in the presence of the calcium sulfate hemihydrate), solidification in a mold or in bulk, and preparing of microbeads by milling and sizing.
  • an inorganic substance such as calcium sulfate hemihydrate and optionally a conditioning agent such as calcium stearate
  • Molds made of stainless steel or teflon can be used to prepare beads, cylinders, spheres (e.g., 3mm in diameter), wafers etc. Microbeads can in turn be compressed into tablets with various binding agents to yield another dosage form.
  • composition is used in the manufacture of top dressing, a feed pellet, etc.
  • Administration of the solid matrix can be by surgical implant, oral, i.p., i.a. or p.a.
  • the liquid injection can be s.c, i.m, or i.p.
  • the administration is done by parenteral injection.
  • Cement lg of calcium sulfate/calcium stearate (1-25% w/w) plus amikacin pamoate (100-320mg) are thoroughly mixed and contacted with 0.6 ml of aqueous dextran sulfate (10% w/v). After blending to a smooth slurry (30s), the material is transferred to a 5ml syringe and installed in vivo where it solidifies. Amikacin sulfate can be blended with amikacin pamoate to adjust the release profile. Presence of the calcium stearate allows for the solidification in the presence of moisture.
  • Beads/Cylinders are thoroughly mixed and contacted with 0.6 ml of a
  • Sterile 3mm beads can be installed individually with mosquito forceps or in groups using a cannula.
  • a teat cannula is a safe tool for installation of beads and cylinders. This approach has been successfully used in the treatment of squamous cell carcinoma via intralesional chemotherapy with 3mm beads of the invention containing cw-Pt (7%).
  • cw-Pt cw-Pt
  • Sterile microbeads (45-150microns) (dry) are suspended in a suitable liquid for injection just prior to use.
  • a solution of the antibiotic of choice may be used as the suspending liquid.
  • amikacin solution 3ml/25%) is used to suspend microbeads (300mg) containing amikacin pamoate prepared as described in Example 4.
  • An "initial burst" provided by the soluble amikacin sulfate is followed by the amikacin that elutes from the microbeads.
  • a similar approach is appropriate for creating a subcutaneous depot of antibiotics and other active ingredients.
  • Microbeads are mixed with food or feed.
  • the composition of the invention is tasteless and in some cases will mask the taste of a bioactive compound.
  • the microbeads of the invention can be included in a capsule for oral delivery.
  • the delivery system in the form of microgranules or other shapes is added to or mixed with food or feed (as used herein the term "feed” includes food).
  • the delivery system is tasteless and odorless and in some cases will mask the taste of a bioactive compound.
  • the delivery system can be added to or mixed with pet food, human food (treat for a companion animal), sweet feed, (a mixture of molasses, cracked corn, oats, etc), fish food, and poultry feed mixes.
  • the delivery system is added or sprinkled on top as a top-dressing and advantageously, the delivery system is added to moist feed or food so that it does not settle to the bottom of the food or feed container.
  • the delivery system is added to the dry food or feed in a form that will adhere to the food or feed. Dosing is typically 100-300 microgram/kg for ivermectin.
  • the powdered formulation dosed at the same interval and amount accepted in the field, is mixed with the food for a given animal.
  • the delivery system can also be incorporated in a feed pellet, as in the case for livestock, horses, fish, etc.
  • the feed pellet typically includes one or more of ground alfalfa, corn, or other grain.
  • the ingredients are mixed with water and then extruded into a dry pellet, tablet (optionally chewable, or biscuit. Common rabbit feed is an example of a feed pellet form.
  • the feed pellet can also include meat by-products.
  • the ingredients are mixed in a slurry, and pressed into a pellet or tablet for administration.
  • the delivery system can also be incorporated in a salt or mineral block, as in the case for livestock, deer, elk etc.
  • the block typically includes sodium chloride, minerals and the delivery system.
  • feeding is advantageously achieved by mixing the active agent composition (such as ivermectin) with sweet feed.
  • active agent composition such as ivermectin
  • sweet feed usually a one pound can of molasses- containing grain mix is adequate. Fasting overnight prior to morning feeding can be beneficial. Care should be taken to assure that the horse gets the medicated feed. Usually this is achieved by isolating dominant horses or horses that eat very fast and then bother other horses. Feeding horses in individual box stalls (enclosures) eliminates the concern for one horse getting too much or too little. Nose bags can also be employed.
  • One embodiment of the invention is a dry, micro-granular formulation of ivermectin that is administered by mixing with the horse's grain ration, preferably in sweet feed although other moist formulations will work as well.
  • Feeding of livestock is accomplished by mixing the delivery system with feed as a top dressing or as a pre-mix, or incorporating the delivery system in a feed pellet for dosing. This mixture of the delivery system in large quantities of feed is then fed to cattle or other ruminants on an individual basis.
  • This method improves palatability and is an alterative to injectable parasiticide formulations or oral "gun" dosing of a liquid. The method can be used with cattle, sheep and goats.
  • Feeding of wildlife such as deer or elk can be achieved in the same manner as for livestock or by using a salt or mineral block.
  • the delivery system including the active ingredient such as ivermectin is administered by spreading it on the housing floor as grit.
  • 3mm beads are colorized (eg red) to increase demand by the birds.
  • the delivery system is included in the pelletized feed.
  • the delivery system (including eg ivermectin) is applied, for example, in a microgranular form at the recommended dosage, as a top dressing, or mixed with the animals' food, or added to a human food product and given to the pet as a treat.
  • the invention presents an advantage to the pet owner in ease of administration and acceptance of the treatment such as monthly heartworm treatment (ivermectin pyrantel)(all year round).
  • the pet can receive the delivery system, which includes the active ingredient in a number of ways:
  • the delivery system is incorporated in a feed pellet for administration.
  • Disodium pamoate (865mg) was dissolved in a minimum amount of water.
  • Amikacin sulfate (782 mg), dissolved in a minimum amount of water, was added to the sodium pamoate solution and mixed thoroughly at room temperature. The precipitate was collected by filtration and washed with two portions (5ml) of cold water. The material was dried in a vacuum dessicator for 48 hrs. Yield: 70 %. MP: 235-244 degrees C with decomposition.
  • Disodium Pamoate (216mg) was dissolved in a minimum amount of water.
  • Clindamycin- HC1 (461 mg), dissolved in a minimum amount of water, was added to the sodium pamoate solution and mixed thoroughly at room temperature. The precipitate was collected by filtration and washed with two portions (5ml) of cold water. The material was dried in a vacuum dessicator for 48 hrs. Yield: 78 %. MP: 189-194 degrees C.
  • Calcium sulfate and calcium stearate powders were thoroughly mixed in a weight ratio of 19/1. This mixture (lg) was then blended with finely ground enrofloxacin (160mg). To this solid mixture was added 0.6ml of polyethyleneglycol solution (PEG-MW 8,000, 10%w/v). The slurry was mixed for one minute and then allowed to solidify in bulk or was injected into a teflon mold for the production of 3mm beads.
  • PEG-MW 8,000, 10%w/v polyethyleneglycol solution
  • Calcium sulfate and calcium stearate powders were thoroughly mixed in a weight ratio of 19/1. This mixture (0.8g) was then blended with finely ground cefoperazone (200mg). To this solid mixture was added 0.6ml of polyethyleneglycol solution (PEG-MW 8,000, 10%w/v). The slurry was mixed for one minute and then allowed to solidify in bulk or was injected into a teflon mold for the production of 3mm beads.
  • PEG-MW 8,000, 10%w/v polyethyleneglycol solution
  • Cefoperazone microbeads were prepared as described in Example 6 (solidification in bulk). Milling and sieving the solid matrix produced the microbeads. Microbeads (lOOmg) were incubated in 0.4 ml of PBS, pH 7.4 at 37C. The PBS buffer was changed at 24-hour intervals over a 4-day period and the samples were analyzed for eluted drug either spectrophotometrically or by microbiological assay. Results are shown below.
  • Lameness was grade 5 — non-weight-bearing.
  • Prior therapy included systemic treatment with penicillin and gentamicin without effect.
  • the joint fluid showed elevated protein and WBC.
  • a suspension containing 300 mg of amikacin pamoate microbeads was injected through an 18-gauge needle. The horse showed rapid improvement and the joint fluid was found to be sterile at day three. At five days post treatment, the horse was ,sound.
  • a mixed-breed dog (20 lb, age 5) was treated for a chronic respiratory infection with clindamycin pamoate.
  • the formulation of clindamycin-pamoate was co-administered with unformulated clindamycin pamoate to provide a long-lasting depot.
  • Finely ground clindamycin pamoate (lOOmg) was mixed with the formulation of clindamycin pamoate (1.7g, Example 5). The mixture was suspended in sterile water and injected, s.c, in two portions on either side of the neck. The animal was asymptotic after four days.
  • Disodium Pamoate 54 mg was dissolved in a minimum amount of water.
  • Doxycycline-HCI 120 mg was added to the sodium pamoate solution and mixed thoroughly at room temperature. The precipitate was collected by filtration and washed with two portions (5 ml) of cold water. The material was dried in a vacuum dessicator for 48 hors. Yield: 85%. MP: 190-196°.
  • Fibrinogen can be used as the matrix polymer when thrombin is included in the formulation — thrombin converts fibrinogen to fibrin which polymerizes. The amount of thrombin and fibrinogen can be adjusted to provide a gelation time that is longer than the setting time of the inorganic matrix. This sequence results in a matrix within a matrix.
  • throombin (lmg) is mixed with 4.7 g of calcium sulfate/calcium stearate (19/1) to yield a stock (solid) solution. This solid is then diluted, as appropriate, to give 0.1 units of thrombin/gram of calcium sulfate/calcium stearate.
  • Erythropoietin (4.5mg) is mixed with lg of calcium sulfate/calcium stearate/thrombin (0.1 units). To this solid is added 300ul of a solution containing fibrinogen (6%) and serum albumin (5%). The fibrinogen/serum albumin solution is made with Hepes buffer (0.03M, pH 7.2). After 48 hrs the hard solid is milled and sized to 45-150 microns.
  • Ivermectin (HOmg) was finely ground and combined with calcium sulfate hemihydrate (890mg) that contained 5% calcium stearate w/w. After thorough mixing, 0.6ml of polyethyleneglycol solution (PEG-MW 8,000, 10%w/v) was added. After solidification, the product was allowed to stand for 24 hr, milled and sized (45-150 microns). The material ( "Ivermectin System”) was used to successfully deworm horses at a dosage of ivermectin of 200 mcg/kg. Table 2. Treatment of parasites in naturally infected horses — eggs per gram of feces as a function of time. EPG was determined at Day-5, day 7, and day 14. Five animals were included in each group.
  • Subject Group ( animals) day-5 day 7 day 14 day 28
  • ivermectin preparations Two groups of horses (mixed breed, ages 5-15, weights 800- 13001b) were treated with ivermectin preparations to demonstrate the relative efficacy of the preparation. Five days before administration fecal samples were taken for determination of Strongyl eggs per gram (EPG). At day 0 ivermectin was administered at a dosage of 200ug/kg. Eqvalan (Merial) paste was administered as directed. Ivermectin System was sprinkled of sweet feed and mixed prior to feeding. The top-dressed feed was well accepted by the horses and was completely consumed. Sweet feed is a commercial product of mixed grains and nutrients which is impregnated with molasses. The Ivermectin System powder sticks to molasses and is incorporated into the mix. For a 12501b horse 1.68g of powder are used with lib of sweet feed. Results are shown in below.
  • EPG eggs per gram
  • Subject Group (5 animals each) day -5 day +7 dav +14
  • Plasma concentrations were determined using HPLC following administration of Eqvalan paste and two versions of Ivermectin System. Blood samples (6) were drawn at timed intervals and analyzed for ivermectin. Ivermectin System 1 compared favorably with Eqvalan. This preparation contained PEG-8000 as the matrix polymer. Ivermectin System 2 contained PS 80 as the matrix polymer. These results demonstrate the ability to control the distribution of active ingredient. More ivermectin is relation in the digestive tract with PS 80 as the matrix polymer as compared to the formulation containing the PEG-8000.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne en général la production et l'utilisation de complexes composés inorganiques-agents modificateurs servant à réguler la libération de composés comprenant des produits médicinaux. De manière avantageuse, le produit inorganique utilisé est le sulfate de calcium et l'agent modificateur est le stéarate de calcium.
PCT/US2002/021646 2001-07-31 2002-02-26 Nouvelles methodes et formulations concues pour administrer des agents actifs WO2003011214A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011641A2 (fr) * 2003-07-28 2005-02-10 Mallinckrodt, Inc. Composition de stearate amelioree et procede
WO2006023035A2 (fr) * 2004-07-28 2006-03-02 Mallinckrodt Inc. Composition de stearate amelioree et procede
WO2008075979A2 (fr) * 2006-12-21 2008-06-26 Bomac Research Limited Formulation d'un comprimé
US8124118B2 (en) 2003-10-22 2012-02-28 Lidds Ab Composition comprising biodegradable hydrating ceramics for controlled drug delivery
US9731490B2 (en) 2008-10-02 2017-08-15 Mylan Inc. Method for making a multilayer adhesive laminate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3781268A (en) * 1972-01-27 1973-12-25 Bristol Myers Co Antibiotic derivatives of kanamycin
WO1999015150A1 (fr) * 1997-09-22 1999-04-01 Buford Biomedical, Inc. Complexes inorganiques-polymeres utiles pour une liberation controlee de composes comprenant des composes medicinaux
US6497901B1 (en) * 2000-11-02 2002-12-24 Royer Biomedical, Inc. Resorbable matrices for delivery of bioactive compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3781268A (en) * 1972-01-27 1973-12-25 Bristol Myers Co Antibiotic derivatives of kanamycin
WO1999015150A1 (fr) * 1997-09-22 1999-04-01 Buford Biomedical, Inc. Complexes inorganiques-polymeres utiles pour une liberation controlee de composes comprenant des composes medicinaux
US6497901B1 (en) * 2000-11-02 2002-12-24 Royer Biomedical, Inc. Resorbable matrices for delivery of bioactive compounds

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7456306B2 (en) 2003-07-28 2008-11-25 Mallinckrodt Inc Stearate composition and method of production thereof
CN100379408C (zh) * 2003-07-28 2008-04-09 马林克罗特公司 改进的硬脂酸盐组合物及制备方法
US7385068B2 (en) 2003-07-28 2008-06-10 Mallinckrodt Inc. Stearate composition and method
WO2005011641A3 (fr) * 2003-07-28 2005-04-14 Mallinckrodt Inc Composition de stearate amelioree et procede
WO2005011641A2 (fr) * 2003-07-28 2005-02-10 Mallinckrodt, Inc. Composition de stearate amelioree et procede
US8124118B2 (en) 2003-10-22 2012-02-28 Lidds Ab Composition comprising biodegradable hydrating ceramics for controlled drug delivery
US9034359B2 (en) 2003-10-22 2015-05-19 Lidds Ab Composition comprising biodegradable hydrating ceramics for controlled drug delivery
WO2006023035A2 (fr) * 2004-07-28 2006-03-02 Mallinckrodt Inc. Composition de stearate amelioree et procede
WO2006023035A3 (fr) * 2004-07-28 2006-06-15 Mallinckrodt Inc Composition de stearate amelioree et procede
GB2458593A (en) * 2006-12-21 2009-09-30 Bomac Research Ltd Tablet formulation
GB2458593B (en) * 2006-12-21 2011-05-04 Bomac Research Ltd Anthelmintic tablet formulations
WO2008075979A3 (fr) * 2006-12-21 2008-07-31 Bomac Research Ltd Formulation d'un comprimé
US8835397B2 (en) 2006-12-21 2014-09-16 Bayer New Zealand Ltd. Macrocyclic lactone tablet formulation
WO2008075979A2 (fr) * 2006-12-21 2008-06-26 Bomac Research Limited Formulation d'un comprimé
US9731490B2 (en) 2008-10-02 2017-08-15 Mylan Inc. Method for making a multilayer adhesive laminate
US10272656B2 (en) 2008-10-02 2019-04-30 Mylan Inc. Method for making a multilayer adhesive laminate

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