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WO2000032167A1 - Polysome - Google Patents

Polysome Download PDF

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Publication number
WO2000032167A1
WO2000032167A1 PCT/US1999/027980 US9927980W WO0032167A1 WO 2000032167 A1 WO2000032167 A1 WO 2000032167A1 US 9927980 W US9927980 W US 9927980W WO 0032167 A1 WO0032167 A1 WO 0032167A1
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WO
WIPO (PCT)
Prior art keywords
polymer
medicament
polysome
lipid
weight percent
Prior art date
Application number
PCT/US1999/027980
Other languages
English (en)
Other versions
WO2000032167A9 (fr
Inventor
John R. Lau
Original Assignee
Sdg, 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 Sdg, Inc. filed Critical Sdg, Inc.
Priority to AU19219/00A priority Critical patent/AU1921900A/en
Publication of WO2000032167A1 publication Critical patent/WO2000032167A1/fr
Publication of WO2000032167A9 publication Critical patent/WO2000032167A9/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • This invention relates to a pharmaceutical polysome. More particularly, it relates to a medicament delivery system comprising a liposome matrix and a medicament-polymer complex which is associated with or incorporated into the liposome matrix.
  • a problem in administering therapeutic agents or medicaments, such as biogenic primary amines, e.g., 5-hydroxytryptamine hydrochloride (5-HT HC1) and y- amino-n-butyric acid (GABA) and cytokines, hormones, biologically active proteins and enzymes for replacement therapy contained in a pharmaceutical delivery system to a patient in need thereof, is the leakage of the therapeutic from such a system into the external media of a patient's body. This leaking results in undesirable physiological responses, pharmacological side effects and an adverse effect on the therapeutic index of such therapeutic agent or medicament.
  • biogenic primary amines e.g., 5-hydroxytryptamine hydrochloride (5-HT HC1) and y- amino-n-butyric acid (GABA) and cytokines, hormones, biologically active proteins and enzymes for replacement therapy contained in a pharmaceutical delivery system to a patient in need thereof.
  • a need exists for a pharmaceutical delivery system which will deliver a desired medicament in a pharmacologically effective and safe dose to a patient in need thereof, whereby such system prevents or substantially minimizes the interaction of the medicament in the body of the patient with non-target receptor sites.
  • a selected medicament e.g., a biogenic amine
  • This invention relates to a polysome and, more particularly, to a polysome comprising a liposome matrix and a medicament-polymer complex associated therewith or incorporated thereinto.
  • the liposome matrix is obtained by reacting or combining a lipid binding agent with a selected lipid or a mixture of lipids. The resultant liposome then binds, via the binding agent, the medicament-polymer complex to the liposome.
  • R.E.S. reticulo-endothelial system
  • Figure 1 is a depiction of poly(maleic anhydride- 1-octadecene) derivatized with 5-HT HC1;
  • Figure 2 is a plot of a dose response of portal serotonin.
  • polysome has been coined to designate a novel composition of matter which is a reaction product of a selected liposome and a selected polymer.
  • a "pharmaceutical polysome” is a polysome having a selected medicament associated with or incorporated into the reaction product of the liposome and the polymer and optionally contains natural or amine derivatized target molecules and R.E.S. avoidance molecules derivatized in a similar fashion.
  • a suitable polymer is selected.
  • a suitable polymer is one which can react with and bind a suitable selected medicament thereto as well as react with and be bound to a lipid binding agent, e.g.
  • phosphatidylethanoleamine contained in the liposome.
  • the polymer can also react and bind biologically active proteins and pharmaceuticals which express primary amines.
  • the polymer provides multiple attachment sites for regulating the stoichiometric binding relationships between target molecules, reticulo-endothelial system avoidance molecules, medicaments or therapeutics and lipid membrane binding agents.
  • a suitable polymer is a poly (maleic anhydride- 1-octadecene), poly (maleic anhydride- 1-hexadecene), poly (maleic anhydride- 1-tetradecene), poly (maleic anhydride- 1-dodecene).
  • the poly (maleic anhydride- 1-octadecene) polymer is employed.
  • poly(maleic anhydride- 1-octadecene) polymer having a molecular weight of 30,000 to 50,000, where the molecular weight of a single functional polymeric unit thereof, which includes the anhydride functional unit and the octadecylhydrocarbon chain, is 350 as shown in Figure 1. Accordingly, in this polymer there are approximately 86 to 143 functional units available in a single polymer chain which can participate in chemical reactions.
  • a suitable polymer is one which reacts by means of an anhydride functional group.
  • Other nucleophilic addition reactions may be obvious to those skilled in the art.
  • a suitable medicament is any medicament which reacts with and binds to the selected polymer.
  • Such medicaments include pharmacologically active compounds containing a primary amine molecule.
  • the medicament is selected from the class of neuro transmitters designated as biogenic primary amines. Such amines
  • 5-hydroxytryptamine hydrochloride or serotonin 5-HT HC1
  • L- ⁇ -3,4-HT HC1 5-hydroxytryptamine hydrochloride or serotonin
  • l-(aminomethyl) cyclohexane acetic acid (gabapentin), biologically active cytokines,
  • TNF tumor necrosis factor
  • the medicament can be selected from hematopoietic growth factors, e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, erythropoietin and also chemotherapeutic agents, e.g., doxorubicin and daunorubicin, antisense oligonucleotides and other medicaments, such as antimicrobials, antivirals and antibiotics.
  • hematopoietic growth factors e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, erythropoietin and also chemotherapeutic agents, e.g., doxorubicin and daunorubicin, antisense oligonucleotides and other medicaments, such as antimicrobials, antivirals
  • medicaments which are reactive with a diamine such as ethylenediamine and target molecules which contain one or more free acid groups, such as N(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DID A), etc.
  • DID A N(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid
  • such medicaments as proteins, hormones, and enzymes can be reacted with a diamine, e.g., ethylenediamine, using an appropriate carbodiimide coupling agent whereby the monoamine derivative is obtained.
  • This monoamine derivative can then be reacted with the polymer, e.g., poly(maleic anhydride- 1-octadecene) to become bound thereto to form a desired medicament-polymer complex or reaction product.
  • the polymer e.g., poly(maleic anhydride- 1-octadecene)
  • the same principle applies for attaching other carboxylic acid derivatives of the iminodiacetic acid class of targeting molecules as well as R.E.S. avoidance molecules, e.g., pegylated amino terminal derivatives of the polyethylene glycol class of molecules which can be used to selectively coat the surface of a circulating polysome by molecular attachment to a polymer of the poly(maleic anhydride) class of hydrocarbon polymers.
  • the selected medicament e.g. 5-HT HC1
  • a molar excess of the polymer e.g. poly(maleic anydride- 1-octadecene)
  • the molar ratio of a poly (maleic anydride- 1-octadecene) polymer, having a molecular weight of 30,000 to 50,000, to the 5-HT HC1 is 3:1.
  • the reaction of the medicament and polymer is typically carried out at a temperature ranging from 20° C to 60° C for 0J5 to 1.5 hours until all the medicament has reacted with the limited portion of the polymer, e.g., to form a monoamide or multiple amide bonding patterns as determined by a fluorescamine analytical assay for primary amino group functionalities.
  • a fluorescamine analytical assay for primary amino group functionalities e.g., a fluorescamine analytical assay for primary amino group functionalities.
  • Other acceptable analytical assays for primary amines groups can be also employed.
  • the amount of the polymer which is employed is sufficient to partially react with the medicament and also to react partially with the binding agent, e.g. PE, which is incorporated in the liposome to which the medicament polymer complex is destined to be associated, i.e. bound to or incorporated into.
  • the poly(maleic anhydride- 1- octodecene) polymer is present at a preferred amount ranging from 11.5% to 34.7% by weight of the total lipid concentration of the liposome to which the medicament- polymer complex is destined to be bound or to be incorporated into. Higher or lower concentrations of polymer may be used depending on the chemical conditions of the reaction process and the desired amount of medicament.
  • the therapeutic agent or medicament is first added to the polymer in order to achieve the desired stoichiometry in the reaction mixture. For example, for
  • 5-HT HC1 the stoichiometry is a 3:1 mole ratio of poly(maleic anhydride- 1- octadecene) polymer to 5-HT HC1. This represents on a mole basis 117 ⁇ moles of the polymer for every 39J ⁇ moles of 5-HT HC1 as illustrated in EXAMPLE 1.
  • a binding agent is selected.
  • a suitable binding agent is one which (1) will react with or combine with or be mixed with a lipid or a mixture of lipids to form a liposome incorporating this agent, and (2) upon such incorporation is capable of reacting with the medicament-polymer complex to bind the complex to or to incorporate the complex into the liposome.
  • Some suitable agents include phosphatidylethanolamine (PE), stearylamine, phosphatidylserine and additional phosphatidyl amino acids expressing a primary amine.
  • PE phosphatidylethanolamine
  • PE phosphatidylethanolamine
  • PE phosphatidylethanolamine
  • the selected binding agent e.g., PE
  • a lipid or a lipid mixture at a temperature of 20° C to 80° C for 0J5 to 2.0 hours to form a liposome following hydration of the lipid.
  • a suitable lipid is selected from 1,2- distearoyl-sn-glycerol-3-phosphocholine (DSL), cholesterol (CHOL), a dicetyl phosphate (DCP) and the chromium (bis) [N-(2,6- diisopropylphenylcarbamoylmethyl) iminodiacetic acid] target molecule or a mixture of any of the forgoing.
  • DSL 1,2- distearoyl-sn-glycerol-3-phosphocholine
  • cholesterol CHOL
  • DCP dicetyl phosphate
  • chromium bis
  • lipid selected from either l,2-distearoyl-sn-glycerol-3-phosphocholine (DSL), 1,2-dipalmitoyl-sn- glycerol-3-phosphocholine (DPL), 1 J-dimyristoyl-sn-glycerol-3-phosphocholine (DML) or other such similar compounds.
  • DSL l,2-distearoyl-sn-glycerol-3-phosphocholine
  • DPL 1,2-dipalmitoyl-sn- glycerol-3-phosphocholine
  • DML 1 J-dimyristoyl-sn-glycerol-3-phosphocholine
  • the desired polysome construct is formulated by initiating a reaction sequence emphasizing competition reactions between poly(maleic anhydride- 1-octadecene), 5- HT HC1 and phosphatidylethanolamine.
  • 5-HT HC1 is first reacted with a limited portion of the available maleic anhydride residues residing in the poly(maleic anhydride- 1-octadecene) polymer.
  • the newly formed polymeric construct which is suspended in aqueous media, is mixed with the dried lipid constituents to initiate a reaction between membrane-bound phosphatidylethanolamine and some of the remaining maleic anhydride functional groups in the polymer.
  • the product of this maleylation reaction creates another amide linkage
  • the resultant medicament-polymer complex comprising medicament, e.g., 5-
  • HT HCl covalently bound through an amide linkage to the polymer, e.g., poly(maleic anhydride- 1-octadecene) is suspended in a suitable aqueous solvent, e.g., deionized water, a physiologically acceptable buffer or phosphate buffered saline at pH 7.4 to form a complex suspension.
  • a suitable aqueous solvent e.g., deionized water, a physiologically acceptable buffer or phosphate buffered saline at pH 7.4 to form a complex suspension.
  • the specified lipids e.g., the PE combined with a lipid or a mixture of the designated lipids is dried typically at 40° C to 80° C for 0.5 to 2.5 hours and the suspension is hydrated therewith at 25° C to 80° C for 0.5 to 2.0 hours to react the incorporated binding agent with the polymer moiety of the previously referenced complex in order to bind or incorporate the complex to or into the
  • reaction between some of the remaining available reaction sites of the polymer with the binding agent e.g., PE this occurs via another amide linkage, as determined by an analytical assay using either fluorescamine or another methodology for detecting primary amine functionalities.
  • the resultant pharmaceutical polysome provides a pharmaceutical delivery system which retards the movement or desorption of the polymer covalently bound to the medicament, e.g. 5-HT HCl, from the liposome or lipid containing matrix, via additional bonding between the medicament-polymer complex and the incorporated
  • the medicament selected to be used is one not having an amine group in its structural formula, but which is reactive with an amine group
  • such medicament is first partially reacted with a suitable diamine, e.g. ethylene diamine, as previously discussed, to obtain a free monamine derivative of the medicament.
  • a suitable diamine e.g. ethylene diamine, as previously discussed
  • This derivative is then reacted with the polymer and the resultant complex is then reacted with the liposome, as previously described, to form the desired pharmaceutical liposome.
  • the incorporated or lipid linked binding agent e.g. phosphatidylethanolamine or PE, provides a good anchoring site for the polymer, e.g. poly(maleic anhydride- 1- octadecene), typically through the amide bond and secondarily through van der
  • Effective amounts of the polysomes of the present invention may be administered to a subject by one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions.
  • the polysomes of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the polysomes may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should contain at least 0.01% of the medicament, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 0.01% to about 70% of the weight of the unit.
  • the amount of the medicament present in such compositions is such that a suitable dosage will be obtained.
  • compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 0J to 300 miligrams of the medicament.
  • the tablets, pills, capsules, troches and the like may also contain the following adjuvants: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid,
  • a lubricant such as magnesium stearate or Sterotex
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl sahcylate or orange flavoring.
  • a liquid carrier such as fatty oil.
  • Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes, and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the polysomes of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.01% of the medicament, but may be varied to be between 10% and about 50% of the weight thereof. The amount of the medicament present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations are prepared so that a parenteral dosage unit contains between 5.0 to 100 milligrams of the medicament contained in the polysome.
  • the solutions or suspensions may also include the following adjuvants: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustments of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl paraben
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • 5-HT HCl was incorporated, via the complex with the poly(maleic anhydride -1-octadecene) polymer, into the liposome at a concentration of 2.0 mg/ml
  • the liposomal constituents were then evaporated under water aspiration by employing slow turning of the sample using a B ⁇ chi Rotoevaporator for 30 minutes at 60° C and then under high vacuum for 2 hours at 60° C using a Jouan Vacuum Pump equipped with a 105°C cold trap to remove any residual chloroforrmmethanol solvent. Then 41.0 mgs (117 ⁇ moles of poly(maleic anhydride- 1-octadecene) (molecular weight 30,000 to 50,000, a product of Polysciences, Inc.) was added to a second container and dissolved with 10 mis of the chloroform:methanol 2:1 (v/v) stock solution. In order to create a dried polymer film, the polymer was evaporated under water aspiration for 30 minutes at 60° C by employing slow turning of the sample using the B ⁇ chi
  • the polymer and 5-HT HCl suspension were transferred to a separate container containing 5.0 mgs (7.0 ⁇ moles) of PE along with 113J mgs of the remaining lipid constituents (TABLE I).
  • This mixture which contained all the lipid components, the polymer and the radiolabeled 5-HT HCl was then hydrated for 45 minutes at 60° C at high rpm using the B ⁇ chi Rotoevaporator.
  • four separate 1.0 ml aliquots of the suspension containing lipid, polymer and 2,000 ⁇ g of 5-HT HCl/ml were then sonicated at 60° C for one minute each on setting #4 of the
  • Tekmar #TM375 Sonicator The resultant suspension exhibited a milky white appearance.
  • 1.0 ml of the resultant polysome suspension was placed in a Slide- A-Lyzer® 10K dialysis cassette, 10,000 MWCO from Pierce Chemical Co., and was dialyzed against 300 mis of 50 mM Tris HCl buffer pH 8.8 for about 24 hours. The dialysate was changed several times until a negligible number of radiolabeled 5-HT HCl molecules were observed in the external bulk phase media or dialysate.
  • the particle size of the resultant polysome was 89.5 nm as determined by a Coulter N4 Plus Particle Size Analyzer.
  • the ratio of polymer to 5-HT HC was 48.9 ⁇ moles to 37.6 ⁇ moles (1.28:1).
  • the respective ⁇ molar ratios of the polymer, 5-HT HCl and PE was 48.0:37.6:7.0.
  • EXAMPLE 4 The procedure of EXAMPLE 3 was employed, except that 1.0 ml of the suspension from EXAMPLE 3 was put in a Slide-a-Lyzer cassette, as discussed in EXAMPLE 1. The sample was then dialyzed against 300 mis of 50 mM Tris buffer pH 8.8. The dialysate was changed three times, using 300 mis of fresh buffer each
  • EXAMPLE 10 In this example the weight amounts of the individual lipid constituents were scaled up 1.2 times for expediency in obtaining a larger sample size. All the lipid mole ratios remained constant.
  • This polymer and 5-HT HCl suspension of 10 mis was transferred to the first container which contained the dried lipids of 6 mgs (8 ⁇ moles) of PE and 136.0 mgs of the remaining lipid constituents (TABLE I).
  • This mixture of lipids, polymer and the radiolabeled 5-HT HCl was then hydrated for 45 minutes at 60° C at high rpm using the B ⁇ chi Rotoevaporator.
  • 10 mis of the mixture was sonicated in 1.0 ml aliquots for one minute on setting #4 of the Tekmar #TM375 Sonicator at 60° C. The aliquots were pooled and the polysome suspension appeared milky- white with no visible particles.
  • 1.0 ml of the polysome suspension containing 350 ⁇ g of 5-HT HCl was placed in a Spectra/Por CE Dialysis Tube (MWCO 10K) from Spectrum, and dialyzed against 1,000 mis of 50 mM phosphate buffer pH 7.0.
  • the dialysate was changed after 24 hours, 72 hours and 35 days and analyzed for radiolabeled 5-HT HCl in the bulk phase media.
  • the particle size of the resultant polysome was 113J nm as determined by a Coulter N4 Plus Particle Size Analyzer.
  • the free 5-HT HCl in the dialysate was measured to be 299 ⁇ g (85%) and the polysome-bound 5-HT HCl in the retentate was 28 ⁇ g (8%>) for a total recovery of 93%.
  • the 5-HT HCl polysome of EXAMPLE 10 was tested in a normal dog to observe the effect on portal vs hepatic glucose balance as a function of the dose of polysomal serotonin administered.
  • the dose is calculated as the amount of free base 5-HT delivered.
  • the graph in Figure 2 illustrates the results.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un polysome comprenant un polymère lié par un agent de liaison à une matrice lipidique. Le polysome peut être un polysome pharmaceutique contenant un médicament lié au polymère. Lorsque le polymère est un poly(-1-octadécène d'anhydride maléique), un agent de liaison approprié est la phosphatidyl éthanolamine. Les médicaments typiques contiennent des amines primaires biogéniques.
PCT/US1999/027980 1998-12-01 1999-11-26 Polysome WO2000032167A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19219/00A AU1921900A (en) 1998-12-01 1999-11-26 A polysome

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11033898P 1998-12-01 1998-12-01
US60/110,338 1998-12-01

Publications (2)

Publication Number Publication Date
WO2000032167A1 true WO2000032167A1 (fr) 2000-06-08
WO2000032167A9 WO2000032167A9 (fr) 2001-12-13

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Application Number Title Priority Date Filing Date
PCT/US1999/027980 WO2000032167A1 (fr) 1998-12-01 1999-11-26 Polysome

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AU (1) AU1921900A (fr)
WO (1) WO2000032167A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006013042A3 (fr) * 2004-08-05 2006-06-01 In Johann Wolfgang Goethe Uni Chelateurs polyvalents pour la modification et l'organisation de molecules cibles
EP3360540A1 (fr) * 2007-09-28 2018-08-15 SDG, Inc. Structures à base lipidique et à biodisponibilité orale
US10751418B2 (en) 2007-09-28 2020-08-25 Sdg, Inc. Orally bioavailable lipid-based constructs
US11071715B2 (en) 2017-03-13 2021-07-27 Sdg, Inc. Lipid-based nanoparticles and methods using same
US11077173B2 (en) 2017-03-13 2021-08-03 Sdg, Inc. Lipid-based nanoparticles and methods using same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZALIPSKY S. ET AL: "Peptide Attachement to Extremities of Liposomal Surface Grafted PEG Chains: Preparation of the Long-Circulating Form of Laminin Pentapeptide, YIGSR", BIOCONJUGATE CHEMISTRY, vol. 6, no. 6, 1995, pages 705 - 708, XP002927215 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006013042A3 (fr) * 2004-08-05 2006-06-01 In Johann Wolfgang Goethe Uni Chelateurs polyvalents pour la modification et l'organisation de molecules cibles
US9606114B2 (en) 2004-08-05 2017-03-28 Johann Wolfgang Goethe-Universitat Frankfurt Am Main Multivalent chelators containing a scaffold structure for modifying and organizing of target molecules
EP3360540A1 (fr) * 2007-09-28 2018-08-15 SDG, Inc. Structures à base lipidique et à biodisponibilité orale
US10568835B2 (en) 2007-09-28 2020-02-25 Sdg, Inc. Orally bioavailable lipid-based constructs
US10751418B2 (en) 2007-09-28 2020-08-25 Sdg, Inc. Orally bioavailable lipid-based constructs
US11517529B2 (en) 2007-09-28 2022-12-06 Sdg, Inc. Orally bioavailable lipid-based constructs
US11071715B2 (en) 2017-03-13 2021-07-27 Sdg, Inc. Lipid-based nanoparticles and methods using same
US11077173B2 (en) 2017-03-13 2021-08-03 Sdg, Inc. Lipid-based nanoparticles and methods using same

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WO2000032167A9 (fr) 2001-12-13
AU1921900A (en) 2000-06-19

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