WO1999058111A1 - Methodes permettant d'utiliser des vehicules a base de lipides pour l'administration de medicaments - Google Patents

Methodes permettant d'utiliser des vehicules a base de lipides pour l'administration de medicaments Download PDF

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Publication number
WO1999058111A1
WO1999058111A1 PCT/US1999/009915 US9909915W WO9958111A1 WO 1999058111 A1 WO1999058111 A1 WO 1999058111A1 US 9909915 W US9909915 W US 9909915W WO 9958111 A1 WO9958111 A1 WO 9958111A1
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Prior art keywords
agent
lipid
agents
liposomes
composition
Prior art date
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Ceased
Application number
PCT/US1999/009915
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English (en)
Inventor
Michael F. Wendland
Philipp Lang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leland Stanford Junior University
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Leland Stanford Junior University
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Publication date
Application filed by Leland Stanford Junior University filed Critical Leland Stanford Junior University
Publication of WO1999058111A1 publication Critical patent/WO1999058111A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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

Definitions

  • Liposomes are made of molecules with hydrophilic and hydrophobic ends that form spherical lipid bilayers, either unilamellar or multilamellar, enclosing a polar, usually aqueous medium.
  • hydrophilic agents can be entrapped in the interior of the medium
  • hydrophobic agents can be entrapped in the lipid bilayer component.
  • the first and second lipid compositions are administered over the course of a dosing event, where a dosing event is defined as the administration of the agent/lipid composition and the agent free lipid composition(s).
  • a dosing event might actually include the administration of four distinct lipid compositions over a period of time, but only one of the lipid compositions will be a lipid/agent composition.
  • the treatment protocol includes four different dosing events.
  • the number of lipid compositions i.e. agent/lipid compositions and agent free lipid compositions
  • the first and second lipid compositions may be administered at the same time or at different times. As such, the lipid compositions may be administered substantially simultaneously or sequentially. Where the lipid compositions are administered sequentially, i.e. at different times, the order in which the compositions are administered may vary. Thus, the lipid composition that includes the agent may be administered to the host before the lipid composition that is free of the agent. Conversely, the lipid composition that includes the active agent may be administered after the lipid composition that is free of the agent.
  • two or more agent free lipid compositions are administered to the host in a given dosing event, with at least one agent free lipid composition administered before and after the lipid/agent composition, such that the lipid/agent composition is administered between administrations of the agent free lipid composition.
  • the first and second lipid compositions may be administered at substantially the same time, including simultaneously, during a given dosing event (as mentioned above), in many preferred embodiments, the first and second lipid compositions are administered at different times.
  • the agent free lipid composition is administered to the host at least once prior to administration of the lipid/agent composition, where the number of times the agent free composition is administered may range from about 1 to 20, usually from about 1 to 5 times prior to administration of the lipid/agent composition (i.e. the lipid composition carrying the therapeutic agent).
  • the agent free lipid composition is administered at least once, usually at least twice and more usually at least three times prior to the lipid/agent composition, where the period of time between administrations may be as great as 1 to 6 hrs, but will usually not exceed about 7 days.
  • the time period between administration of the agent free lipid composition and the agent/lipid composition may vary, but typically will range from about 3 hours to 7 days, usually from about 24 to 72 hours and more usually from about 24 to 48 hours.
  • the overall treatment protocol may include a heat treatment step.
  • the host may undergo one or more preliminary heat treatments, such as local mild heating to the external surface, eg. by warm bath or heating suit, to increase distribution of the agent free lipid composition into the skin prior to administration of the lipid/agent composition.
  • This type of therapeutic approach reduces agent accumulation in non-target tissue, thereby reducing the occurrence and/or severity of adverse or toxic reactions to the agent, e.g. foot hand syndrome, etc.
  • ultrasound treatment Another treatment which may be incorporated into the overall treatment region is ultrasound treatment.
  • the ultrasound will typically be localized to one or more target tissues, e.g. organs, in which lipid composition accumulation is desired.
  • target tissues e.g. organs, in which lipid composition accumulation is desired.
  • Means of applying ultrasound to a host are known in the art, and include those described in U.S. Patent Nos. 5,409,002; 5,143,073; 5,111,822; 5,080,102; 5,080,101; 5,065,761; 5,065,741; and 5,060,650; the disclosures of which are herein incorporated by reference.
  • the lipid structures are generally single layer or bilayer lipid structures arranged in roughly spherical or elliptical shapes, although other shapes including irregular shapes are also possible, where the lipids are generally surface active lipids that may either be ionic or nonionic. Within the lipid structures themselves, the individual lipid molecules are
  • the liposomes can be modified to modulate their expected in vivo half-life, e.g. the half-life may be extended by attaching biologically inert polymers to the liposome surface, such as polyethylene glycol (PEG), and the like, to produce prolonged circulation liposomes.
  • the surface may be modified to present one or more targeting moieties that serves to direct the liposome to its target under in vivo conditions, where such targeting moieties include antibodies, receptor ligands and the like.
  • targeting moieties include antibodies, receptor ligands and the like.
  • Therapeutic agents are agents that have a desirable pharmacologic activity and are therefore useful in a particularly therapeutic treatment regimen, where therapeutic agents of interest include anti-inflammatory agents, antibacterial agents, antimicrobial agents, chemotherapeutic agents (antineoplastic agents), antiviral agents, antifungal agents, immunotherapeutic agents, gene therapy agents (e.g. nucleic acids encoding a product of therapeutic value) and the like, where the agent may be a nucleic acid, e.g. DNA, RNA, antisense, peptide nucleic acid, ribozymes, etc, a proteins, a peptides, an organic small molecule, and the like.
  • therapeutic agents of interest include anti-inflammatory agents, antibacterial agents, antimicrobial agents, chemotherapeutic agents (antineoplastic agents), antiviral agents, antifungal agents, immunotherapeutic agents, gene therapy agents (e.g. nucleic acids encoding a product of therapeutic value) and the like, where the agent may be a nucleic acid, e.g
  • both agents can be carried by different lipid/agent compositions or the same lipid/agent composition. If the same lipid/agent composition is used, both agents may be present in the interior of the lipid structure or both agents may be present on the exterior of the lipid structure or both agents may be incorporated into the lipid layer of the lipid structure. Alternatively, one agent may be present in the interior of the lipid structure and one agent may be present on the exterior of the lipid structure or one agent may be present in the interior of the lipid structure and one agent is incorporated into the lipid layer of the lipid structure or one agent is present on the exterior of the lipid structure and one agent is incorporated into the lipid layer of the lipid structure.
  • first and second lipid compositions are administered to the host, usually at different times.
  • the agent or agents will be incorporated into the structure of lipid component, e.g. sequestered in the interior, present on the surface, or present in the bilayer of a liposome.
  • these compositions will not comprise the agent which is present in the lipid/agent compositions used in the invention, i.e. they will not comprise the same biologically active agent.
  • the agent free lipid compositions are empty, i.e. these lipid compositions comprise nothing but structural lipid, e.g. an empty liposome, or have one or more biologically inactive or inert compounds associated with it, e.g. sequestered within in it or present on the surface, where these biologically inactive or inert compounds play no role in the treatment regimen being performed.
  • the lipid components of the lipid compositions are generally the same type of structure, e.g. they are both liposomal, micellar, LCM etc. While the lipid components of the lipid compositions are the same type of structure, they may differ from each other compositionally and/or physically.
  • the lipid component of each of the compositions may be liposomal, but the liposomes of the first composition may have a different diameter than the liposomes of the second composition.
  • the liposomes of the first composition may be non- surface modified liposomes, where the liposomes of the second composition may be surface modified to change plasma half-life, tissue half-life, tissue uptake, extra- and intracellular
  • Desired results in the subject methods can be achieved by selecting lipid compositions with specific compositional and/or physical characteristics, as well as the proper order of administration. In other words, by tailoring the physical or compositional characteristics of the lipid compositions and selecting the proper order of administration, desired results can be obtained.
  • empty liposomes can be injected prior to therapeutic agent comprising liposomes to decrease tissue accumulation of therapeutic agent loaded liposomes in non- target tissue and at least diminish accumulation of therapeutic agent in these tissues.
  • additional treatments such as temperature modulation, e.g. hypothermia, heat treatment, etc. may be employed.
  • the target tissue can be treated after administration of the empty liposomes to readily uptake the subsequently administered drug loaded liposomes.
  • Treatments of interest include: hypothermia treatment, ultrasound shock wave treatment, radiation treatment and the like, where such protocols are known to those of skill in the art and have been described in greater detail supra.
  • Another means of improving the selectivity of agent uptake by the target tissue and to decrease systemic agent toxicity is to administer agent free liposomes comprising antibodies to normal tissue on their surface first, followed by administration of agent loaded liposomes modified with target tissue antibodies.
  • Representative routes of administration include: intravenous injection, intracavitary instillation, intraperitoneal injection, intraventricular injection, pleural injection, intraarticular injection, lymphatic injection, intraarterial injection, intratumoral injection, inhalation, etc.
  • intravenous injection intracavitary instillation
  • intraperitoneal injection intraperitoneal injection
  • intraventricular injection pleural injection
  • intraarticular injection lymphatic injection
  • intraarterial injection intratumoral injection, inhalation, etc.
  • the lipid compositions are systemically administered.
  • a particularly preferred means of administration are means for introducing the lipid compositions directly into the circulatory system of the host, e.g. intraarterial or intravenous injection means.
  • a particularly preferred means of administration is intravenous, especially in those embodiments in which the two different lipid compositions are administered at substantially the same time or simultaneously.
  • the dosage of the lipid composition that comprises the active agent will necessarily depend on the specific nature of the agent, the condition to be treated, the target tissue and the nature of the lipid component of the composition. Nevertheless, the dosage of the agent/lipid composition will be one that is effective to achieve a desired result, e.g. treatment of the condition, cessation or amelioration of a symptom, and the like. For any given specific agent/lipid composition and condition to be treated, the dosage can be determined empirically. As far as the dosage of agent free lipid composition is concerned, depending on the desired outcome, this composition may be administered at tissue saturating dose (i.e. the liposome concentration at which further dose increases do not results in additional liposome accumulation in the target tissue), below tissue saturation dose or above tissue saturation dose.
  • tissue saturating dose i.e. the liposome concentration at which further dose increases do not results in additional liposome accumulation in the target tissue
  • tissue saturation dose i.e. the liposome concentration at which further dose increases do not results in additional liposome accumulation in the
  • Administration of an agent in accordance with the subject methods results in improved results as compared to a control situation.
  • the specific nature of the improved results necessarily depends on the type of agent being administered, but may include one or more of: enhanced target specificity; a longer retention of agent at a desired target site; a reduced dosage requirement; longer intervals between dosages; reduced toxicity; and the like.
  • control situation is meant administration of the agent by a method other than the subject invention, such as by drug loaded liposome alone, free agent alone, etc.
  • those embodiments of the subject invention that result in improved results as compared to administration of agent/lipid composition by itself.
  • Improved results are obtained by the subject invention in many embodiments as administration of an agent according to the subject results in an altered biodistribution of the agent as compared to a control situation, where the altered biodistribution yields improved results, such as enhanced distribution of the agent to the target tissue(s), where specific target tissues to which delivery of the agent is enhanced by the subject methods include: neoplasms, breast cancer tissue; pediatric tumors, e.g.
  • kits for use in the subject methods are also provided.
  • the kits according to the subject invention at least comprise a lipid composition that includes agent and a lipid composition free of agent, where the agent may be a diagnostic agent, a therapeutic agent, etc..
  • EXPERIMENTAL A Four rats bearing osteogenic sarcoma were studied: two animals received only a single injection of 110 nm liposomal Gd-DTPA-BMA (dose of 0.05 mmol/kg body weight Gd- DPTA-BMA)(control group) via the rats' tail vein. Two animals received injection of 110 nm liposome encapsulated Gadolinium (dose of 0.05 mmol/kg body weight Gd-DTPA-BMA) immediately followed by injection of liposome encapsulated doxorubicin (Doxil, Sequus Pharmaceuticals, Menlo Park, CA)(dose of 4 mg/kg body weight)(treatment Group). The two animals in the treatment group received repeat injections of liposome encapsulated docorubicin 2 and 4 days after the initial injection using the same dose. Liposomes with 110 nm liposomal Gd-DTPA-BMA (dose of 0.05 mmol/kg body weight Gd- DPTA-BMA)(control group) via the
  • both animals demonstrated prominent enhancement of the tumor 24 hours after injection comparable to that seen in the control group.
  • contrast enhancement was seen to persist for the entire observation period: the tumors were still brightly enhanced at 3 days, 4 days, 5 days and 6 days after injection.
  • Each group consists of six tumor bearing animals. Both groups receive the same initial injection of liposomes with encapsulated Gd-DTPA-BMA at a dose of 0.05 mmol/kg body weight followed by liposomes with encapsulated doxorubicin at a dose of 2 mg/kg body weight. However, group 2 is injected with empty liposomes on days 2, 4, 6 and 8 after the initial injection. The retention of liposomes with encapsulated agent by the tumor is then observed in the two groups and compared. It is expected that at least one of the following occurs: (a) a persistent enhancement of the tumor in Group 2 beyond 24 hours that is greater
  • Group 2 a conventional empty liposomes liposomes liposomes liposomes liposomes with liposomes with b 6 hours later liposomes with with with prolonged prolonged prolonged circulation time loaded prolonged prolonged circulation circulation with Gd-DTPA-BMA &l ⁇ posomes circulation circulation time loaded time loaded with prolonged circulation time time loaded time loaded with with loaded with doxorubicin with with doxorubicin doxorubicin doxorubicin doxorubicin doxorubicin
  • Each group consists of 6 tumor bearing rats. Each group gets the same dosage schedule of doxorubicin liposomes with prolonged circulation time and liposomes with prolonged circulation time loaded with Gd-DTPA-BMA. Groups 2 and 3 additionally receive empty conventional liposomes designed to load normal tissues with empty liposomes. These liposomes have a brief circulation time and are not appreciably taken up by tumor. Using this approach, accumulation of drug liposomes is inhibited in normal liver, spleen and reticuloendothelial tissue thereby reducing adverse reactions. Accumulation/retention of drug liposomes in liver, skin, and tumor is determined on MRI images. In addition, production of skin rash or other signs of hand-foot syndrome is monitored for each group. Groups 2 and 3 exhibit less skin rash, lower quantities of drug liposome in liver, but similar quantities delivered to the tumor, based on MRI evaluation.
  • Group 1 receives the chemotherapeutic regimen with free, unencapsulated doxorubicin at the standard dose.
  • Group 3 receives the chemotherapeutic regimen with liposomes with prolonged circulation time with encapsulated doxorubicin at the same doxorubicin dose used for the free drug; however, additionally, empty liposomes with prolonged circulation time are injected every 24 hours for 5 days and starting 24 hours after each therapeutic agent/liposome injection using the same lipid dose that is employed for liposomes with encapsulated doxorubicin.
  • Group 3 then receives the chemotherapeutic regimen with liposomes with prolonged circulation time with encapsulated doxorubicin at the same doxorubicin dose used for the free drug; additionally, empty liposomes with prolonged circulation time are injected every 24 hours for 5 days and starting 24 hours after each therapeutic agent/liposome injection using the same lipid dose that is employed for liposomes with encapsulated doxorubicin.
  • Patients in Group 3 demonstrate (a) a better therapeutic efficacy, i.e. more extensive central tumor necrosis and more pronounced arrest of tumor growth, than patients in Groups 1 and 2. However, additionally, patients in Group 3 demonstrate a lower incidence of hand foot syndrome than patients in Group 2.
  • the subject invention provides for a number of advantages over conventional liposome based delivery protocols in which only agent loaded liposomes are administered without re-injection of empty liposomes.
  • Such advantages include one or more of reduced dosage requirements, longer time intervals between dosages and reduced host toxicity.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes et des compositions qui permettent d'administrer des agents à un hôte au moyen de vecteurs à base de lipides. Les méthodes consistent à administrer audit hôte une composition lipidique renfermant l'agent et une composition lipidique dépourvue d'agent, généralement à des moments différents. Dans de nombreux modes de réalisation, la composition lipidique est une composition à base de liposomes. Les méthodes de l'invention présentent, en ce qui concerne l'administration de l'agent, certains avantages tels que diminution du dosage, toxicité réduite, ciblage plus spécifique, etc.
PCT/US1999/009915 1998-05-08 1999-05-07 Methodes permettant d'utiliser des vehicules a base de lipides pour l'administration de medicaments Ceased WO1999058111A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8477298P 1998-05-08 1998-05-08
US60/084,772 1998-05-08

Publications (1)

Publication Number Publication Date
WO1999058111A1 true WO1999058111A1 (fr) 1999-11-18

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5023087A (en) * 1986-02-10 1991-06-11 Liposome Technology, Inc. Efficient method for preparation of prolonged release liposome-based drug delivery system

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5023087A (en) * 1986-02-10 1991-06-11 Liposome Technology, Inc. Efficient method for preparation of prolonged release liposome-based drug delivery system

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