WO1992020323A1 - Methods for the administration of drugs - Google Patents
Methods for the administration of drugs Download PDFInfo
- Publication number
- WO1992020323A1 WO1992020323A1 PCT/US1991/003420 US9103420W WO9220323A1 WO 1992020323 A1 WO1992020323 A1 WO 1992020323A1 US 9103420 W US9103420 W US 9103420W WO 9220323 A1 WO9220323 A1 WO 9220323A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amphotericin
- lipid
- mice
- liposomes
- drag
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Definitions
- Lipid associated drug particles such as liposomes (also known as vesicles) are used in drug delivery systems to target drugs to particular areas of the body, to prevent toxic drags from coming into contact with healthy, sensitive tissues, and to increase the half-life of drags in the blood and/or other organs of the body.
- Liposomes are subcellular particles comprised of one or more spherical lipid bilayers which surround an internal aqueous space. Drags may be encapsulated either within the internal aqueous space or in the lipid bilayer, which is usually composed of a phospholipid such as saturated or unsaturated phosphatidylcholine, some type of sterol, and various other, charged or neutral, natural or synthetic lipids.
- liposomes serve to extend the effectiveness of a drug by delaying the release of the encapulated drag.
- early intravenous formulations extended the half-life of the free drug in circulation by the delayed release from the liposomes as the vesicles were slowly metabolized.
- Some applications involve the use of liposomes to provide the gradual topical release of the drag, followed by the delivery of the released free drag across a dermal or mucosal membrane to enter the blood or lymph system.
- liposomal drag formulations require the delivery of the intact liposome encapsulated drug unit to the blood or lymph.
- some liposome formulations target anticancer drags to tumors, and the circulation of the intact liposome in the bloodstream is instrumental in the increased efficacy of the formulation.
- Other drag containing liposomes are taken up by the macrophages in the body or the reticuloendothelial system and delivered to the site of infection, and the drug without the encapsulating vesicle does not have this characteristic.
- topical application has not been the same as direct intravenous infusion since only the free drag, rather than the intact liposome, has been systemically delivered.
- lipid particles especially those including lipid associated drags and preferably intact liposomes encapsulating the drags, may be systemically administered to the body of a mammal, Le., delivered internally (to the circulation, either blood or lymph) by mucocutaneous administration.
- mucocutaneous refers to the mucosal surfaces of the vagina and the anus, which are composed of stratified squamous epithelia.
- the invention is thus a method comprising the systemic delivery of intact lipid particles to the blood or lymph of a mammal by the application of lipid particles having a size of less than 250 nm to the mucocutaneous tissue of the mammal, or the use of lipid particles having a size of less than 250 nm in the preparation of a composition for systemically delivering intact lipid particles to the blood or lymph of a mammal by the application of the composition to the mucocutaneous tissue of the mammal.
- the lipid particles encapsulate an active agent which is systemically delivered as part of the intact particle, and the lipid particles are preferably liposomes, most preferably unilamellar vesicles (UVs) having a diameter of from 30 to 200 nm.
- UVs unilamellar vesicles
- This method is advantageous in that it can permit the placement of intact liposomes containing an active agent (ie., a therapeutic or diagnostic agent) in the intestinal tract, without exposure to damaging gastric constituents.
- an active agent ie., a therapeutic or diagnostic agent
- the liposomes are transmitted intact and distributed to other parts of the body (for example to the liver, kidney or spleen) either through the bloodstream or lymphatic system. Macrophages may engulf the liposomes and enable circulation to sites of inflammation throughout the body. Mucocutaneous, preferably rectal, ad ⁇ ninistration of these lipid particles is a non-invasive method to effectively deliver drag to deep organs of the body to treat systemic conditions.
- lipid bilayer vesicles are closed microscopic vesicles which are formed principally from individual molecules having a polar (hydrophilic) and a non-polar (lipophilic) portion, although cholesterol and other sterols may be included if desired.
- the hydrophilic groups can be phosphato, glycerylphosphato, carboxy, sulfato, amino, hydroxy, choline or other polar groups.
- non-polar groups are saturated or unsaturated hydrocarbons such as alkyl, alkenyl or other lipid groups. Liposomes are a subset of these bilayer vesicles and are comprised principally of phospholipid molecules.
- each side of the membrane presents a hydrophilic surface while the interior of the membrane comprises a lipophilic medium.
- These membranes in the presence of excess water, can initially be arranged in a system of concentric closed membranes, in a manner which is not dissimilar to the layers of an onion, around an internal aqueous space.
- Each of the membranes is an unbroken, bilayer sheet of lipid molecules.
- MLVs multilamellar vesicles
- the technical aspects of liposome formation are well known in the art, as is the fact that liposomes are advantageous for encapsulating biologically active substances.
- Liposome preparations may be used in the manner of the invention by application to mucosal tissue as an aqueous liposomal dispersion, or in other forms which are known in the art, e.g., suppositories.
- the drag-containing lipid particles could be mixed with melted Witepsol tm in any of the following forms: as a powder after initial spray drying of the lipid-drag organic phase (Le., as proliposomes which form unilamellar vesicles upon exposure to mucocutaneous moisture); as a liquid after microemulsification; or as a powder after drying (e.g., lyophilization) of a UV dispersion.
- Witepsol (glycerol trilaurate) is a liquid at 37°C and becomes a solid at room temperature. Witepsol is commonly used as a vehicle for drag suppositories since it liquefies at body temperature while producing little or no irritation of the rectum. Vaginal suppositories could be prepared similarly. In all applications, the amount to be administered to human patients which is effective for such treatment will be apparent to those of ordinary skill in the art. While I do not wish to be bound to a particular theory, it is thought that the M cells located along the intestinal microvilli of the rectum are responsible for the liposome uptake in this area. These M cells are found near the intestinal goblet cells.
- the difference between these cells is that the goblet cells secrete mucin to prevent particulate penetration whereas the M cells are specialized to engulf particles (250 nm or less) in the intestinal lumen and deliver them to the Peyer's patches underlying the intestinal epithelium.
- the Peyer's patches are specialized immune structures present in high numbers throughout the subcutaneous tissue of the intestines. These patches consist of localized accumulations of lymphocytes and macrophages in which the immune response to foreign antigens can take place. Macrophages leave the Peyer's patches, bearing the liposomal encapsulated therapeutic agent, and enter the circulation for systemic delivery.
- Mucocutaneous tissue ie., the mucosal surfaces of the vagina and the anus, are composed of stratified squamous epithelia. These epithelia lack a horny layer and contain Langerhans cells in a density similar to that of the epidermis. Langerhans cells endocytose the particles, internalize them, leave the epidermis through the basement membrane and migrate into lymph channels. They eventually reach the draining lymph node where they then reside. This may be another mechanism for systemic delivery of lipid-associated particles, such as amphotericin intercalated unilamellar liposomes, when applied on the mucocutaneous surface of the vagina and rectum.
- lipid-associated particles such as amphotericin intercalated unilamellar liposomes
- Systemic fiingal infections are a major cause of mortality in cancer patients and other immunocompromised individuals.
- the preferred treatment for systemic fungal infections is primarily limited to two groups of drugs: the fungicidal polyene antibiotics such as amphotericin B (referred to as amphotericin) and nystatin, and primarily fungistatic imidazoles, such as ketaconazole, miconazole and fluconazole.
- liposomal amphotericin formulations of a particular size, which are useful in the practice of this invention.
- the liposomal amphotericin employed in the following examples comprises unilamellar vesicles having a diameter of less than 250 nm, preferably from 30 to 250 nm, and most preferably from 30 to 100 nm.
- liposomes having a diameter of less than 250 nm may be produced by methods which are known in the art. Briefly, phospholipids are dissolved in an organic solvent and dried to form a film or powder, which is then hydrated with an aqueous solution. The resultant dispersion is subjected to a high shear force, such as sonication, which agitates the dispersion to form smaller vesicles.
- the dispersion is sheared in a modified Gaulin microemulsifier such as is described in EP 0190050.
- a modified Gaulin microemulsifier such as is described in EP 0190050.
- the liposomes employed in the examples were formed according to the method described in more detail in EP0317120, which is incorporated herein by reference, by first fo ⁇ ning a soluble complex between the drag and a phosphatidylglycerol (preferably distearoyl-phosphatidylglycerol) in an acidified organic solvent having a pH of 4.5 or less, preferably from 1.0 to 3.0, as measured on prewetted pH paper.
- a phosphatidylglycerol preferably distearoyl-phosphatidylglycerol
- the complex is formed by dissolving amphotericin B, or another polyene such as a tetraene, pentaene, or hexaene, in a 1:1 (by volume) chloroform:methanol solution, and acidifying the solution with approximately one mole of acid for each mole of amphotericin. Complex formation is facilitated by briefly warming the solution to about 65°C.
- the amphotericin-phospholipid complex while in solution in a small amount of the organic solvent (Le., containing the drag in an amount of at least 7 and preferably 10 mg drag per ml of solvent), is mixed with a phosphatidylcholine and a sterol such as cholesterol and dried to yield a lipid powder which is processed (by the application of shearing force) in a low ionic strength saccharide aqueous buffer solution into stable unilamellar liposomes having a diameter of less than 0.2 .
- the aqueous buffer solution must have a pH such that the pH of the final solution is from 5.5 or less, preferably from 45 to 5.5.
- the amphotericin will have a positive charge and the phosphatidylglycerol will have a negative charge.
- the phosphatidylglycerol and the amphotericin will form a strong association.
- the liposomes formed in this manner can be lyophilized and stored for later rehydration and injection without significant change in size or toxicity.
- all known systemic uses of liposomal or lipid complexed polyene antibiotics have been by injection, e.g., intravenous administration.
- the powder was processed into liposomes by hydration at a concentration of 40 mg/ml in 9% sucrose (w/v) containing 10 mM sodium succinate at pH 5.5 warmed to 65°C for 77 minutes. Shearing force to form small unilamellar vesicles was then provided by a modified Gaulin emulsifying device at a pressure of up to 10,000 psi for 30 minutes to reduce the mean liposome diameter to 31 nm as measured by dynamic laser light scattering. Following sterilizing 0.2 ⁇ filtration, the amphotericin containing liposomes were analyzed for drag content and in-process loss of amphotericin was found to be 10.4%.
- the liposome dispersion was heated at 65°C for ten minutes.
- the LD ⁇ of this liposome preparation in several groups of C57BL/6 mice has been found to be greater than 150 mg/kg, with no deaths in a group of five animals injected at this dose. This is compared to an LD ⁇ for free amphotericin of about 2.3 mg/kg in the same mouse strain.
- Example 2 C57BL/6 female mice were injected intravenously with a lethal dose of
- mice/group Three groups of mice (5 mice/group) were treated intravenously with one of the following: 0.75 mg/kg free amphotericin B, or 0.75 mg/kg or 5.0 mg/kg (amphoUVs). Two other groups of mice (5 mice/group) were treated rectally with one of the following:
- mice 5 mg/kg free amphotericin B, or 5 mg/kg amphoUVs.
- One group of control mice was given intravenous phosphate buffered saline. Treatments were continued daily for five days, and 2 weeks post-infection, the mice were sacrificed, their kidneys removed, homogenized and plated to determine yeast clearance expressed as colony forming units (CFU) /mg kidney.
- CFU colony forming units
- the amphotericin intercalated unilamellar vesicle preparation of Example 1 was delivered as the rehydrated liposome preparation both intravenously and rectally.
- the mice were first anesthetized with ketamine and acepromazine to inhibit peristaltic response.
- the aqueous liposome preparation was then delivered past the sphincter into the anesthetized mice without stimulating ejection of the material.
- Example 3 The same groups of mice with a lethal dose of Candida albicans were given an intraperitoneal injection with sRBC (4 x 10 7 cells) two days post-infection and again on day 10 post-infection. When the mice were sacrificed two weeks post- infection, the spleens were removed and homogenized. The splenic white blood cells were separated from the other tissue cells by centrifugation in a density gradient composed of 4 ml of neutrophil isolation medium layered beneath 6 ml of spleen homogenate diluted in RPMI tissue culture medium. The splenic white blood cells contain a high percentage of B lymphocytes, some T lymphocytes and macrophages.
- the number of B lymphocytes which produced anti-sRBC antibody was determined by using the white blood cell suspension in a modified Jerne plaque assay. In this assay, each B lymphocyte which produces anti-sRBC antibodies will lyse surrounding sRBC when cultured on a monolayer of sRBC. The lysed area will appear as a clear area or a plaque in the RBC monolayer.
- mice 4xl0 7 cells on day 0 and day 7 of the experiment.
- three groups of mice (4 mice/group) were also treated intravenously with one of the following: PBS buffer, 0.75 mg/kg free amphotericin, or 0.9 mg/kg amphoUVs.
- One other group of 4 mice were treated rectally with 5.0 mg/kg amphoUVs. All mice were sacrificed on day 11 at which time a blood sample from each mouse was obtained.
- the spleens were removed, and homogenized and a white blood cell suspension from each group of mice prepared as described above in Example 3.
- the splenic white blood cell suspension was used in the modified Jerne plaque assay to assay the B lymphocyte response to sRBC.
- Each serum sample was assayed for hemagglutinating antibody titer to sRBC.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1991/003420 WO1992020323A1 (en) | 1991-05-16 | 1991-05-16 | Methods for the administration of drugs |
EP19910910068 EP0584063A1 (en) | 1991-05-16 | 1991-05-16 | Methods for the administration of drugs |
JP50945391A JPH06507372A (en) | 1991-05-16 | 1991-05-16 | How to administer the drug |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1991/003420 WO1992020323A1 (en) | 1991-05-16 | 1991-05-16 | Methods for the administration of drugs |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992020323A1 true WO1992020323A1 (en) | 1992-11-26 |
Family
ID=22225533
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/003420 WO1992020323A1 (en) | 1991-05-16 | 1991-05-16 | Methods for the administration of drugs |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0584063A1 (en) |
JP (1) | JPH06507372A (en) |
WO (1) | WO1992020323A1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986005977A1 (en) * | 1985-04-10 | 1986-10-23 | The Liposome Company, Inc. | Steroidal liposomes |
WO1989003677A1 (en) * | 1987-10-27 | 1989-05-05 | Board Of Regents, The University Of Texas System | Liposome-incorporated mepartricin |
EP0317120A1 (en) * | 1987-11-12 | 1989-05-24 | Vestar, Inc. | Improved amphotericin B liposome preparation |
DE4110779A1 (en) * | 1990-03-30 | 1991-10-02 | Poli Ind Chimica Spa | Liposomal formulations for topical esp. vaginal use |
-
1991
- 1991-05-16 EP EP19910910068 patent/EP0584063A1/en not_active Withdrawn
- 1991-05-16 WO PCT/US1991/003420 patent/WO1992020323A1/en not_active Application Discontinuation
- 1991-05-16 JP JP50945391A patent/JPH06507372A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986005977A1 (en) * | 1985-04-10 | 1986-10-23 | The Liposome Company, Inc. | Steroidal liposomes |
WO1989003677A1 (en) * | 1987-10-27 | 1989-05-05 | Board Of Regents, The University Of Texas System | Liposome-incorporated mepartricin |
EP0317120A1 (en) * | 1987-11-12 | 1989-05-24 | Vestar, Inc. | Improved amphotericin B liposome preparation |
DE4110779A1 (en) * | 1990-03-30 | 1991-10-02 | Poli Ind Chimica Spa | Liposomal formulations for topical esp. vaginal use |
Non-Patent Citations (3)
Title |
---|
Chemical Abstracts, vol. 108, no. 16, 18 April 1988, Columbus, Ohio (US), T. Stozek et al.: "Effect of dipyridamole incorporation in liposomes on rectal absorption", see page 391, abstract 137807m, & Acta Pol. Pharm. 1987, 44(2), 206-11 * |
Chemical Abstracts, vol. 99, no. 14, 3 October 1983, Columbus, Ohio (US), N. Sakuragawa et al.: "Basic studies on oral and rectal administration of factor IX concentrate preparation", see page 328, abstract 11607e, & Nippon Ketsueki Gakkai Zasshi, 1983, 46(1), 190-6 * |
Derwent File Supplier WPIL, 1984, AN-84 229071 (37), Derwent Publ. Ltd, London (GB), & JP, A, 59137409 (GREEN CROSS CORP.) 07 August 1984, see the abstract * |
Also Published As
Publication number | Publication date |
---|---|
EP0584063A1 (en) | 1994-03-02 |
JPH06507372A (en) | 1994-08-25 |
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