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WO1993013792A1 - Dispositif de liberation retard de complexes constitues par un metal de transition et une proteine - Google Patents

Dispositif de liberation retard de complexes constitues par un metal de transition et une proteine Download PDF

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Publication number
WO1993013792A1
WO1993013792A1 PCT/US1993/000274 US9300274W WO9313792A1 WO 1993013792 A1 WO1993013792 A1 WO 1993013792A1 US 9300274 W US9300274 W US 9300274W WO 9313792 A1 WO9313792 A1 WO 9313792A1
Authority
WO
WIPO (PCT)
Prior art keywords
pst
amino acid
sustained release
matrix
tubing
Prior art date
Application number
PCT/US1993/000274
Other languages
English (en)
Inventor
Siva N. Raman
Randolph B. De Prince
Aleksander Blum
Original Assignee
Pitman-Moore, Inc.
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 Pitman-Moore, Inc. filed Critical Pitman-Moore, Inc.
Publication of WO1993013792A1 publication Critical patent/WO1993013792A1/fr

Links

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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • This invention relates to sustained release devices capable of delivering protein complexed to transition metals to target animals over a prolonged period of time.
  • U.S. Patent 4,522,625 incorporated herein by reference, relates to an oral drug dispenser comprising a wall formed of a semipermeable material and an enteric material.
  • the enteric material includes amino acids having an isoelectric point below a pH of 7. Amino acids also have proved useful as excipients for the controlled delivery of proteins, including somatotropins.
  • release of protein from some devices is in the form of an initial "burst" with declining amounts thereafter. It would be desirable to have a sustained release device having an improved and
  • the present invention relates to a sustained release device for the release of a biologically active transition metal-protein complex and to methods of administering such a complex-
  • the device is
  • Figure 1 is a schematic representation of an embodiment of an implant in accordance with the present invention.
  • FIG. 2 is a schematic representation of an alternative embodiment of an implant in accordance with the present invention.
  • the present invention relates to a sustained release device for the release of a biologically active transition metal-protein complex after implantation of the device into a target animal.
  • the implanted device includes the transition metal-protein complex in combination with a biologically tolerable transition metal-solubilizing substance, the combination hereafter referred to as the "matrix.”
  • protein including specified proteins such as somatotropin, will include native, synthetic, or recombinant forms of proteins. Additionally, any other variants such as fragments, analogs or other polypeptides having the bioactivity of the corresponding native protein are included. Thus, any transition metal-protein complex could include any of the above variations of that protein.
  • An especially preferred protein is porcine somatotropin.
  • the transition metal used in the present invention can be any suitable transition metal.
  • Such metals are known to those of skill in this art and include, for example, Zn, Mn and Cu.
  • the use of such metals to recover proteins from aqueous solutions is known. See e.g. EPA 0216485A1 incorporated herein by reference.
  • An especially preferred transition metal for use with porcine somatotropin is zinc.
  • Zn-pST will be used as an exemplar. It is to be understood that the exemplary use of Zn-pST is not intended to limit the scope of the invention from its broader applicability to transition metal-protein complexes.
  • amino acids have been found to be suitable solubilizing agents for transition metals.
  • the amino acid combined with the Zn-pST in accordance with this invention is one which enhances the solubility of the Zn-pST and, hence, its release from the device.
  • the amino acid can be a natural or synthetic amino acid. If a natural amino acid, it is preferred that the amino acid contain a basic side chain.
  • the sustained release from the device is effected by providing only a portion of the device with a diffusion barrier while the remainder of the device is impermeable to the matrix, water and other excipients.
  • a cross-section of one embodiment of the present invention is illustrated in Figure 1.
  • An implant device made from non-toxic, innocuous materials is loaded with the Zn-pST matrix in the form of pellets 6, 8, and 10. It is to be understood that it is only this illustrated eiiibodiment which contains 3 pellets. Other embodiments can contain any desirable number of pellets containing the Zn-pST matrix.
  • the sides 2 and 4 of the biotolerable material are impermeable to the matrix, to water or bodily fluids, and to other excipients.
  • biotolerable means any material which can be safely implanted in a biological organism.
  • a length of open-ended silicon tubing forms a satisfactory substance from which to make the device.
  • Other satisfactory substances include various polymers known to those of skill in the art, such as wax or polyethylene.
  • he implant device has ends 11 and 12.
  • one end 11 of the device is also impermeable to, and prevents the escape of, the matrix material.
  • One or more glass beads inserted into one end of a silicon tube provides one effective means for achieving this purpose. Both ends can be permeable if a faster release rate is desired, but typically only one end 12 of the device forms a diffusion barrier.
  • the diffusion barrier can be made from leucine or a microporous polyethylene (“MPPE”) disk.
  • Leucine barriers are preferred. Such barriers can easily be made using simple tableting procedures known to those of skill in the art.
  • a cross-section of a second embodiment of the present invention is illustrated in Figure 2.
  • An implant device is loaded with pellets 6, 8, and 10 of the Zn-pST matrix.
  • the sides and, optionally, one end 14 are impermeable to the matrix, water, bodily fluids and the other excipients.
  • the impermeable portions in this embodiment are made from wax.
  • Suitable waxes include animal waxes, such as beeswax, lanolin, shellac wax, and Chinese insect wax, vegetable waxes such as hydrogenated soybean oil, hydrogenated cottonseed oil, carnauba, candelilla, bayberry, and sugar cane, and mineral waxes such as fossil or earth waxes (ozocerite, ceresin, montan) and petroleum waxes (paraffin,
  • the wax material used in the present invention is beeswax, vegetable wax, carnauba wax, or combinations thereof.
  • At least one end 12 of the .device forms a
  • the Zn-pST used in the invention can be any biologically active form of Zn-pST.
  • Zn-pST will include zinc complexes of native,
  • the Zn-pST desirably is admixed with an amino acid excipient.
  • amino acid will include both natural and synthetic amino acids.
  • Zn-pST has poor solubility in aqueous solutions, such as body fluids, at physiological pH (7.4).
  • one required characteristic of the amino acid is its ability to solubilize the Zn-pST at physiological pH, i.e., amino acids producing a Zn-pST solubilizing effect are required.
  • amino acids which chelate the zinc ion are particularly suitable for use in the present invention.
  • Zn-pST is known to be soluble in alkaline aqueous solutions.
  • amino acids having a basic side chain are preferred.
  • amino acid arginine is particularly preferred.
  • the arginine can be used as a free base or in the form of arginine hydrochloride (AHCl).
  • AHCl is particularly effective in solubilizing recombinant Zn-pST with little or no aggregation. It is to be understood that, armed with the teaching of the present specification, those of skill in the art could readily determine the best excipient-transition metal-protein matrices for any given protein.
  • a synthetic amino acid such as
  • ethylenediaminetetraacetic acid can be admixed with the Zn-pST.
  • EDTA ethylenediaminetetraacetic acid
  • a trisodium salt of the EDTA is used.
  • Table 1 illustrates that much less EDTA, as compared th natural basic amino acids, is required to solubilize the Zn-pST. It is to be understood that other synthetic amino acids can be used in the present invention, providing such amino acids solubilize Zn-pST at physiological pH.
  • sucrose has been used as a
  • sucrose can be included in the matrix of the present invention.
  • ratios of Zn-pST to amino acid to sucrose are from about 1:3:1 to about 1:1:3, respectively, with 1:3:1 being especially preferred.
  • EDTA When EDTA is to be used, larger amounts o Zn-pST can be included in the device. Ratios of Zn- pST to EDTA can range from about 2:1 to about 10:1, respectively.
  • the sucrose in the embodiment utilizin EDTA preferably varies from about 6 parts to about 30 parts by weight.
  • the materials to be used in the matrix are sieved to a particle size of less than about 250 microns prior to being mixed together.
  • Mixing can be a physical mixing with the dry ingredients in the desired ratio placed into a sterile vial and agitated.
  • Methods of agitation are known to those of skill in the art and include, for example, the use of vortex shakers.
  • a suitable agitation time typically is from about 5 to about 10 minutes. After about 3 minutes, if desired, 1% magnesium stearate, which functions as a tablet lubricant, can be added to the formulation.
  • a second desirable method of preparation involves colyophilization.
  • the desired amount of Zn-pST is added to an aqueous solution of the desired amounts of amino acid and sucrose.
  • the resulting solution is sonicated for a few minutes, typically for about 5 to 10 minutes. After filtering through a 0.22 micron filter the solution is
  • the resulting mixed powders from either mixing procedure preferably are pelleted. Suitable methods of pelleting are known to those of skill in the art and include the use of a Stoke's machine or a single punch press. The weight and size of the pellets can be controlled with such techniques. It has been found that pellets having diameters of from about 3.0 to 4.0 mm give preferred release characteristics. Especially preferred are pellets having about 4 mm diameters. The length of the pellet can vary but typically is about 7 mm.
  • a desired number of the resulting pellets are inserted into a sustained release device suitable for implantation into a target animal. This number will be governed in part by the amount and duration of the desired dosage. Generally, the sustained release device will be only slightly larger than the number of pellets it is to contain. Any bio-tolerable
  • implantable device can be used.
  • implantable device can be used.
  • silicone tubing is a preferred material. Especially preferred is silicon tubing having an inner diameter of about 4 mm.
  • bioactive somatotropin for several days is preferred.
  • This invention also includes methods of
  • Zn-pST administering Zn-pST to target animals.
  • An implant device containing a desired amount of Zn-pST, as previously described, is implanted into a target animal.
  • Techniques of implantation are known to persons of skill in this art, and any such implantation technique is suitable for use in the present invention.
  • the matrix is solubilized in the target animal's body fluids and the bioactive somatotropin Zn-pST is
  • the somatotropin desirably is released from the device at a sustained rate over the course of several days, preferably at least about 14 days.
  • the present invention also relates to a process for improving the release characteristics of Zn-pST from implantable sustained release devices.
  • Zn-pST is admixed with a substance capable of solubilizing Zn-pST at physiological pH and a desired amount of the mixture is loaded into a sustained release device.
  • Suitable substances include natural amino acids having basic side chains and their salts, such as arginine,
  • the natural amino acid is AHCl and the Zn-pST is a recombinant pST.
  • Zn-pST can be admixed with a synthetic amino acid such as EDTA.
  • Histidine and monosodium glutamate were sterilized by filtration through 0.2 micron Gelman Acrodiscs ® and lyophilized from 3.3 and 10% w/v aqueous solutions respectively.
  • Arginine and AHCl were not sterilized.
  • Alanine and sucrose were autoclaved for 15 minutes and vacuum dried (76 mm) for 36 hours at 40°C. The
  • arginine had been hydrated to a moisture content of 17%. Each ingredient was passed through a 60-mesh sieve prior to mixing. The amounts of each ingredient were directly weighed into tared, sterile vials. The pST was added first, then the amino acid and, lastly, the sucrose.
  • the vials were sealed and agitated on a Vortex- Genie mixer at a setting of 10 while rotating by hand. After three minutes, 1% magnesium stearate which had been autoclaved and vacuum dried was added and the agitation continued for an additional two minutes. The resulting powder was sieved to less than 250 micron particle size and pelleted using a single punch press (Key International, Inc.) fitted with flat punches to give tablets weighing 101 mg, measuring 4.0 mm in diameter and 7 mm in length. Prior to pelleting, all contact surfaces were sterilized by wiping with 70% EtOH, flaming and exposing to UV radiation for 15 minutes. The tooling was lubricated with sterile magnesium stearate after each compression.
  • Example 1 The implants from Example 1 were placed in a
  • spectrophotometer was used to measure the absorbance at 276 nm. A random scattering correction was applied by measuring the absorbance at 320 nm and subtracting this value from that at 276 mm. An extinction coefficient of 0.73mg -1 ml cm -1 was used for the Zn-pST solutions.
  • GPC chromatography

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à un dispositif implantable de libération contrôlée servant à la libération contrôlée d'un complexe constitué par un métal de transition et une protéine. Ledit complexe se combine à une substance augmentant sa solubilité au pH physiologique. L'invention décrit également un procédé servant à améliorer la solubilité de complexes constitués par un métal de transition et une protéine au pH physiologique, ainsi qu'un procédé servant à administrer lesdits complexes à un animal cible. Dans un mode de réalisation préféré, le métal de transition est le zinc et la protéine est une somatotropine porcine.
PCT/US1993/000274 1992-01-13 1993-01-08 Dispositif de liberation retard de complexes constitues par un metal de transition et une proteine WO1993013792A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82017692A 1992-01-13 1992-01-13
US820,176 1992-01-13

Publications (1)

Publication Number Publication Date
WO1993013792A1 true WO1993013792A1 (fr) 1993-07-22

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PCT/US1993/000274 WO1993013792A1 (fr) 1992-01-13 1993-01-08 Dispositif de liberation retard de complexes constitues par un metal de transition et une proteine

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CN (1) CN1074825A (fr)
AU (1) AU3582893A (fr)
MX (1) MX9300139A (fr)
WO (1) WO1993013792A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027980A3 (fr) * 1996-12-20 1998-08-13 Takeda Chemical Industries Ltd Procede de production d'une preparation a liberation prolongee
WO2001062296A3 (fr) * 2000-02-24 2002-05-30 Monsanto Technology Llc Formulations injectables non aqueuses servant a effectuer la liberation prolongee de somatotropine
US6569406B2 (en) 2000-08-07 2003-05-27 Nektar Therapeutics Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation
US6664234B1 (en) 2000-06-30 2003-12-16 Monsanto Technology Llc Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin
US6719992B2 (en) 2000-06-26 2004-04-13 Monsanto Technology Llc Non-aqueous surfactant-containing formulations for extended release of somatotropin
EP2805965A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
EP2805964A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
US9452157B2 (en) 2012-07-06 2016-09-27 Alfa Wassermann S.P.A Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4765980A (en) * 1986-04-28 1988-08-23 International Minerals & Chemical Corp. Stabilized porcine growth hormone
EP0353045A2 (fr) * 1988-07-26 1990-01-31 Rutgers, The State University of New Jersey Dispositifs et procédés pour promouvoir la croissance de la volaille à rôtir
US4917685A (en) * 1986-05-16 1990-04-17 International Minerals & Chem. Corp. Delivery device for the administration of stabilized growth promoting hormones
WO1990011070A1 (fr) * 1989-03-17 1990-10-04 Pitman-Moore, Inc. Dispositif d'administration par liberation controlee de proteines macromoleculaires
US5008112A (en) * 1985-12-16 1991-04-16 International Minerals & Chem. Corporation Device for the extended delivery of diffusible agents
WO1991005548A1 (fr) * 1989-10-10 1991-05-02 Pitman-Moore, Inc. Composition a liberation entretenue pour proteines macromoleculaires

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5008112A (en) * 1985-12-16 1991-04-16 International Minerals & Chem. Corporation Device for the extended delivery of diffusible agents
US4765980A (en) * 1986-04-28 1988-08-23 International Minerals & Chemical Corp. Stabilized porcine growth hormone
US4917685A (en) * 1986-05-16 1990-04-17 International Minerals & Chem. Corp. Delivery device for the administration of stabilized growth promoting hormones
EP0353045A2 (fr) * 1988-07-26 1990-01-31 Rutgers, The State University of New Jersey Dispositifs et procédés pour promouvoir la croissance de la volaille à rôtir
WO1990011070A1 (fr) * 1989-03-17 1990-10-04 Pitman-Moore, Inc. Dispositif d'administration par liberation controlee de proteines macromoleculaires
WO1991005548A1 (fr) * 1989-10-10 1991-05-02 Pitman-Moore, Inc. Composition a liberation entretenue pour proteines macromoleculaires

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027980A3 (fr) * 1996-12-20 1998-08-13 Takeda Chemical Industries Ltd Procede de production d'une preparation a liberation prolongee
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US6399103B1 (en) 1996-12-20 2002-06-04 Takeda Chemical Industries, Inc. Method of producing a sustained-release preparation
WO2001062296A3 (fr) * 2000-02-24 2002-05-30 Monsanto Technology Llc Formulations injectables non aqueuses servant a effectuer la liberation prolongee de somatotropine
US7048938B2 (en) 2000-02-24 2006-05-23 Monsanto Technology Llc Non-aqueous injectable formulations for extended release of somatotropin
US6719990B2 (en) 2000-02-24 2004-04-13 Monsanto Technology Llc Non-aqueous injectable formulations for extended release of somatotropin
US6719992B2 (en) 2000-06-26 2004-04-13 Monsanto Technology Llc Non-aqueous surfactant-containing formulations for extended release of somatotropin
US7037516B2 (en) 2000-06-26 2006-05-02 Monsanto Technology Llc Non-aqueous surfactant-containing formulations for extended release of somatotropin
US6664234B1 (en) 2000-06-30 2003-12-16 Monsanto Technology Llc Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin
US7030091B2 (en) 2000-06-30 2006-04-18 Monsanto Technology Llc Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin
US6838075B2 (en) 2000-08-07 2005-01-04 Nektar Therapeutics Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation
US6569406B2 (en) 2000-08-07 2003-05-27 Nektar Therapeutics Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation
EP2805965A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
EP2805964A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
US9452157B2 (en) 2012-07-06 2016-09-27 Alfa Wassermann S.P.A Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof

Also Published As

Publication number Publication date
CN1074825A (zh) 1993-08-04
MX9300139A (es) 1994-07-29
AU3582893A (en) 1993-08-03

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