EP1267936A2 - Complexes de camptothecine - Google Patents
Complexes de camptothecineInfo
- Publication number
- EP1267936A2 EP1267936A2 EP01914662A EP01914662A EP1267936A2 EP 1267936 A2 EP1267936 A2 EP 1267936A2 EP 01914662 A EP01914662 A EP 01914662A EP 01914662 A EP01914662 A EP 01914662A EP 1267936 A2 EP1267936 A2 EP 1267936A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- cyclodextrin
- camptothecin
- implant
- tumors
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
- B65G21/00—Supporting or protective framework or housings for endless load-carriers or traction elements of belt or chain conveyors
- B65G21/10—Supporting or protective framework or housings for endless load-carriers or traction elements of belt or chain conveyors movable, or having interchangeable or relatively movable parts; Devices for moving framework or parts thereof
- B65G21/14—Supporting or protective framework or housings for endless load-carriers or traction elements of belt or chain conveyors movable, or having interchangeable or relatively movable parts; Devices for moving framework or parts thereof to allow adjustment of length or configuration of load-carrier or traction element
Definitions
- the present invention relates to improved formulations for the administration of certain camptothecin complexes.
- camptothecin 20(S)-camptothecin (CPT), a plant alkaloid, was found to have anticancer activity in the late 1950's. Wall, M. et al., Plant antitumor agents. I. The isolation and structure of camptothecin. a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J. Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall et al., Camptothecin: Discovery to Clinic. 803 Annals of the New York Academy of Sciences 1 (1996). These documents, and all documents (articles, patents, etc.) cited to herein, are incorporated by reference into the specification as if reproduced fully below. The chemical formula of camptothecin was determined to be C 20 H 16 N 2 O 4 .
- CPT itself is insoluble in water.
- the sodium salt of CPT was derived from CPT through opening of the lactone ring using a mild base.
- Clinical trials were then conducted using this hydrosoluble, sodium salt derivative of CPT (CPT Na+), which was administered intravenously. The studies were later abandoned because of the high toxicity and low potency of CPT Na+.
- Gottlieb, J.A., et al. Preliminary pharmacological and clinical evaluation of camptothecin sodium salt (NSC 100880), Cancer Chemother. Rep. 54:461-470 (1979); Muggia. F.M..
- CPT CPT
- CPT and some of its substituted forms elicited differential responses in the cell cycle of nontumorigenic and tumorigenic human cells in vitro.
- CPT and some of its substituted forms are cytostatic for nontumorigenic cells and cytotoxic for tumorigenic cells
- the selective toxicity of the compounds against tumorigenic cells in vitro and in vivo was an especially interesting feature of these drugs.
- 9-Amino-20(S)-Camptothecin (9AC) and 10,11-Methylendioxy-20(S)-Camptothecin (10,11 MD) are capable of having high anticancer activity against human colon cancer xenografts.
- Giovanella, B.C., et al. Highly effective topoisomerase-l targeted chemotherapy of human colon cancer in xenografts, Science 246:1046- 1048 (1989).
- 9-nitrocamptothecin (9NC) has shown high activity against human tumor xenograft models.
- 9NC has a nine position hydrogen substituted with a nitro moiety. 9NC has inhibited the growth of human tumor xenografts in immunodeficient nude mice and has induced regression of human tumors established as xenografts in nude mice with little or no appearance of any measurable toxicity.
- D. Chatterjee et al. Induction of Apoptosis in Malignant and Camptothecin-resistant Human Cells, 803 Annals of the New York Academy of Sciences 143 (1996).
- Other substituted CPT compounds that have shown promise include 7-ethyl-10-hydroxy CPT, and other 7, 9, 10, 11 -substituted compounds.
- CPT compounds contain an ⁇ -hydroxy- ⁇ -lactone ring functionality that may hydrolyze under physiological conditions.
- the lactone moiety may open up easily to yield the carboxylate form, particularly in the presence of human serum albumin (HSA), where 97% of 9NC has been observed as converting to the open lactone form.
- HSA human serum albumin
- Thomas G. Burke Chemistry of the Camptothecins in the Bloodstream: Drug Stabilization and Optimization of Activity, 803 Annals of the New York Academy of Sciences 29 (1996).
- the biological activity of the closed lactone ring form is far greater than the activity of the open lactone ring, carboxylated form.
- Liposomes are small envelopes of fat-like compounds containing an agueous chamber or chambers within.
- the water insoluble compound may be dissolved in the fat-like compound comprising the envelope of the liposome.
- Liposomes have the disadvantage of being preferentially removed from the circulation and retained in the liver and spleen. This limits their desirability. Liposomes also have a number of other disadvantages, including potential liposome instability and possible change in the size of the liposome upon storage. There is therefore a need for compositions, methods, apparatus, and kits that combine the desirable properties of CPT and its substituted forms with the ability to maintain a closed lactone ring structure.
- the invention relates to compositions comprising a camptothecin and an amorphous cyclodextrin, and to related methods, and apparatus.
- the invention relates to a composition comprising a camptothecin and an amorphous cyclodextrin.
- the invention relates to the composition wherein the camptothecin is a substituted camptothecin.
- the invention relates to the composition wherein the substituted camptothecin comprises 9- nitrocamptothecin, 9-aminocamptothecin, 10,11-methylendioxy-20(S)- camptothecin, 7-ethyl-10-hydroxy camptothecin, or another substituted camptothecin that is substituted in at least one of the 7, 9, 10, 11 , or 12 positions.
- the invention relates to the composition of claim 3, wherein the substituted camptothecin comprises 9- nitrocamptothecin, or 9-aminocamptothecin.
- the invention relates to the composition wherein said amorphous cyclodextrin has a degree of substitution of 2 to 7.
- the invention relates to the composition wherein the amorphous cyclodextrin is substantially free of pyrogenic contaminants.
- the invention relates to the composition wherein the amorphous cyclodextrin comprises hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -cyclodextrin, carboxyamidomethyl- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or diethylamino- ⁇ -cyclodextrin.
- the invention relates to the composition wherein the amorphous cyclodextrin comprises hydroxypropyl ⁇ -cyclodextrin.
- the invention relates to the composition wherein the cyclodextrin comprises hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -cyclodextrin.
- the invention relates to the composition wherein the amorphous cyclodextrin comprises a mixture of two or more of ⁇ -, ⁇ -, or ⁇ - cyclodextrin.
- the invention relates to sterile aqueous solutions comprising the composition in a form suitable for parenteral administration.
- the invention relates to the composition wherein the ratio of the weight of camptothecin to the weight of cyclodextrin compound comprises a range between 1 :1 and 1 :2000. In a further aspect, the invention relates to the composition wherein the ratio of the weight of camptothecin to the weight of cyclodextrin compound comprises a range of about 1 :5 to 1 :200. In still another aspect, the invention relates to the composition wherein the ratio of the weight of camptothecin to the weight of cyclodextrin compound comprises a range of about 1 :5 to 1 :50.
- the invention relates to the composition wherein the camptothecin is present in an amount effective to treat undesirable or uncontrolled cell proliferation.
- the invention relates to the composition wherein the undesirable or uncontrolled cell proliferation comprises restenosis, various cancers, insults to body tissue due to surgery, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.
- the invention relates to the composition wherein the various cancers comprise acute myelogenous leukemia, bladder, breast, cervical, cholangiocarcinoma, chronic myelogenous leukemia, colorectal, gastric sarcoma, glioma, leukemia, lung, lymphoma, melanoma, multiple myeloma, osteosarcoma, ovarian, pancreatic, prostrate, stomach, or tumors at localized sites including inoperable tumors or in tumors where localized treatment of tumors would be beneficial, and solid tumors.
- the invention relates to the composition wherein the various cancers comprise pancreatic or colorectal.
- the invention relates to the composition wherein the composition is in a lyophilized form.
- the invention relates to methods of treating undesirable or uncontrolled cell proliferation comprising administering the above-mentioned composition.
- the invention relates to the method wherein the camptothecin is a substituted camptothecin.
- the invention relates to the method wherein the substituted camptothecin comprises 9-nitrocamptothecin, 9- aminocamptothecin, 10,11-methylendioxy-20(S)-camptothecin, 7-ethyl- 10-hydroxy camptothecin, or another substituted camptothecin that is substituted at least one of the 7, 9, 10, 11 , or 12 positions.
- the substituted camptothecin comprises 9-nitrocamptothecin, or 9-aminocamptothecin.
- the invention relates to the method wherein said amorphous cyclodextrin has a degree of substitution of 2 to 7. In still another aspect, the invention relates to the method wherein the amorphous cyclodextrin is substantially free of pyrogenic contaminants. In yet another aspect, the invention relates to the method wherein the undesirable or uncontrolled cell proliferation comprises restenosis, various cancers, insults to body tissue due to surgery, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.
- the invention relates to the method wherein the various cancers comprise acute myelogenous leukemia, bladder, breast, cervical, cholangiocarcinoma, chronic myelogenous leukemia, colorectal, gastric sarcoma, glioma, leukemia, lung, lymphoma, melanoma, multiple myeloma, osteosarcoma, ovarian, pancreatic, prostrate, stomach, or tumors at localized sites including inoperable tumors or in tumors where localized treatment of tumors would be beneficial, and solid tumors.
- the invention relates to the method wherein the various cancers comprise pancreatic or colorectal.
- the invention relates to implants comprising an implant structure and the composition.
- the invention relates to the implant where the implant is a time-release implant.
- the invention relates to the implant where the implant is a gel or polymer implant.
- the invention relates to the implant where the implant is coated and the composition is contained in the coating.
- the invention relates to the implant where the composition is contained within the implant structure.
- the invention relates to the implant where the implant is biodegradable or is formed in situ.
- the invention relates to a method of treatment comprising inserting an implant into a body wherein the implant is the above-mentioned implant.
- the invention relates to a stent comprising the above-mentioned composition.
- camptothecin may be better solubilized in aqueous solution and the lactone ring of camptothecin may be protected from hydrolysis.
- complexes of camptothecin:cyclodextrin may have reduced ulceration effects when administered to a host.
- Camptothecin is believed to intervene in the mechanism of action of the nuclear enzyme topoisomerase I (topo I), arresting cells in the S phase. It is believed that CPT accomplishes this by stabilizing the covalently linked complexes of DNA-topo I (termed cleavable complexes), thus halting the progression of replication forks.
- Preferable indications that may be treated using this invention include those involving undesirable or uncontrolled cell proliferation.
- Such indications include restenosis, various types of cancers such as primary tumors, insults to body tissue due to surgery, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.
- Specific types of restenotic lesions that can be treated using the present invention include coronary, carotid, and cerebral lesions.
- Specific types of cancers that can be treated using this invention include acute myelogenous leukemia, bladder, breast, cervical, cholangiocarcinoma, chronic myelogenous leukemia, colorectal, gastric sarcoma, glioma, leukemia, lung, lymphoma, melanoma, multiple myeloma, osteosarcoma, ovarian, pancreatic, prostrate, stomach, or tumors at localized sites including inoperable tumors or in tumors where localized treatment of tumors would be beneficial, and solid tumors.
- the types of cancer include pancreatic, and/or colorectal.
- Treatment of cell proliferation due to insults to body tissue during surgery may be possible for a variety of surgical procedures, including joint surgery, bowel surgery, and cheloid scarring.
- Diseases that produce fibrotic tissue include emphysema.
- Repetitive motion disorders that may be treated using the present invention include carpal tunnel syndrome.
- An example of cell proliferative disorders that may be treated using the invention is a bone tumor.
- the proliferative responses associated with organ transplantation that may be treated using this invention include those proliferative responses contributing to potential organ rejections or associated complications. Specifically, these proliferative responses may occur during transplantation of the heart, lung, liver, kidney, and other body organs or organ systems.
- compositions and/or methods may be practiced or administered by a variety of routes, and may be administered or coadministered in any conventional dosage form.
- Coadministration in the context of this invention is defined to mean the administration of more than one therapeutic in the course of a coordinated treatment to achieve an improved clinical outcome.
- Such coadministration may also be coextensive, that is, occurring during overlapping periods of time.
- inventive compounds and/or compositions may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
- the compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
- cyclodextrin is meant ⁇ -, ⁇ -, or ⁇ - cyclodextrin. Cyclodextrins are described in detail in U.S. Patent 4,727,064 to Pitha et al.
- Cyclodextrins are cyclic oligomers of glucose; these compounds form inclusion complexes with any drug whose molecule can fit into the lipophile-seeking cavities of the cyclodextrin molecule.
- the amorphous cyclodextrin is preferably substantially free of pyrogenic contaminants.
- the preferable compositions of matter according to the invention for parenteral administration, especially by the intravenous route will be nonpyrogenic.
- Nonpyrogenic preparations according to the invention when administered to a subject, preferably do not cause a febrile (basal body temperature raising) reaction. Although some bacterial endotoxin may be present, the amount is preferably insufficient to elicit a febrile reaction.
- substantially pyrogen free is meant that the cyclodextrin contains less than about 10 U.S. P.
- the cyclodextrin may contain between 0.1 and 5 U.S. P. bacterial endotoxin units per mg, under conditions specified in the United States Pharmacopeia 23.
- amorphous cyclodextrin non-crystalline mixtures of cyclodextrins wherein the mixture is prepared from ⁇ -, ⁇ -, or ⁇ - cyclodextrin.
- the amorphous cyclodextrin may be prepared by non-selective additions, more preferably by alkylation of the desired cyclodextrin species. Reactions may be carried out to yield mixtures containing a plurality of components thereby preventing crystallization of the cyclodextrin.
- Various alkylated and hydroxyalkyl-cyclodextrins may be made, and of course will vary, depending upon the starting species of cyclodextrin and the addition agent used.
- amorphous cyclodextrins suitable for compositions according to the invention are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -cyclodextrin, carboxyamidomethyl- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and diethylamino- ⁇ -cyclodextrin.
- hydroxy- ⁇ -cyclodextrin may be preferable.
- the substituted ⁇ - cyclodextrins may also be suitable, including hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -cyclodextrin.
- the cyclodextrin of the compositions according to the invention may be ⁇ -, ⁇ -, or ⁇ -cyclodextrin.
- ⁇ -cyclodextrin contains six glucopyranose units; ⁇ -cyclodextrin contains seven glucopyranose units; and ⁇ -cyclodextrin contains eight glucopyranose units.
- the molecule is believed to form a truncated cone having a core opening of 4.7-5.3 A, 6.0-6.5 ⁇ and 7.5-8.3 A in ⁇ -, ⁇ -, or ⁇ - cyclodextrin respectively.
- the composition according to the invention may comprise a mixture of two or more of the -, ⁇ -, or ⁇ - cyclodextrins. More preferably, however, the composition according to the invention will comprise only one of the ⁇ -, ⁇ - , or ⁇ - cyclodextrins.
- the particular ⁇ -, ⁇ -, or ⁇ - cyclodextrin to be used with the particular camptothecin to form the compositions according to the invention may be selected based on the known size of the camptothecin and the relative size of the cavity of the cyclodextrin compound. Generally if the camptothecin is relatively large, a cyclodextrin having a larger cavity is used to make the composition according to the invention. Furthermore, if the camptothecin is administered with an excipient it may be desirable to use a cyclodextrin compound having a larger cavity in the composition according to the invention.
- the unmodified ⁇ -, ⁇ -, or ⁇ - cyclodextrins may be somewhat less desirable in the compositions according to the invention because the unmodified forms tend to crystallize and are relatively less soluble in aqueous solutions.
- Most preferable for the compositions according to the invention are the -, ⁇ -, and ⁇ - cyclodextrins that are chemically modified or substituted. Chemical substitution at the 2, 3, and 6 hydroxyl groups of the glucopyranose units of the cyclodextrin rings yields increases in solubility of the cyclodextrin compound.
- cyclodextrins in the compositions according to the invention are amorphous cyclodextrin compounds.
- amorphous cyclodextrin is meant non-crystalline mixtures of cyclodextrins wherein the mixture is prepared from ⁇ -, ⁇ -, or ⁇ - cyclodextrin.
- the amorphous cyclodextrin is prepared by non-selective alkylation of the desired cyclodextrin species. Suitable alkylation agents for this purpose include but are not limited to propylene oxide, glycidol, iodoacetamide, chloroacetate, and 2- diethylaminoethlychloride.
- Reactions may be carried out to yield mixtures containing a plurality of components thereby potentially preventing crystallization of the cyclodextrin.
- Various alkylated cyclodextrins may be made, and of course will vary, depending upon the starting species of cyclodextrin and the alkylating agent used.
- amorphous cyclodextrins suitable for compositions according to the invention are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -cyclodextrin, carboxyamidomethyl- ⁇ - cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and diethylamino- ⁇ -cyclodextrin.
- hydroxypropyl- ⁇ -cyclodextrin is preferable although the ⁇ - or ⁇ - analogs may also be suitable.
- Amorphous hydroxypropyl- ⁇ -cyclodextrin may be purchased from a number of vendors including Cerestar, Inc. (Hammond, Indiana, USA) under the trade name Encapsin, or from Janssen Pharmaceuticals (Beersen, Belgium). In addition, other forms of amorphous cyclodextrin having different degrees of substitution or glucose residue number are available commercially.
- a method for the production of hydroxypropyl- ⁇ - cyclodextrin is disclosed in Pitha et. al., U.S. Patent No.4, 727,064.
- Camptothecin when used in the context of this invention, includes both substituted and unsubstituted camptothecins, and analogs thereof.
- substituted camptothecins when substituted camptothecins are used, a large range of substitutions may be made to the camptothecin scaffold, while still retaining activity.
- the camptothecin scaffold is substituted at the 7, 9, 10, 11 , and/or 12 positions. Such preferable substitutions may serve to provide differential activity over the unsubstituted camptothecin compound.
- Especially preferable are 9- nitrocamptothecin, 9-aminocamptothecin, 10,11-methylendioxy-20(S)- camptothecin, 7-ethyl-10-hydroxy camptothecin, or another substituted camptothecin that is substituted in at least one of the 7, 9, 10, 11 , or 12 positions.
- Native, unsubstituted, camptothecin can be obtained by purification of the natural extract, or may be obtained from the Stehlin Foundation for Cancer Research (Houston, Texas). Substituted camptothecins can be obtained using methods known in the literature, or can be obtained from commercial suppliers. For example, 9- nitrocamptothecin may be obtained from SuperGen, Inc. (San Ramon, California), and 9-aminocamptothecin may be obtained from personal Pharmaceuticals (San Diego, California). Camptothecin and various of its analogs may also be obtained from standard fine chemical supply houses, such as Sigma Chemicals.
- the inventive compositions may include conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive, agents. Additionally, the compositions may include more than one camptothecin and more than one cyclodextrin, and/or additional pharmaceutically active agents. In preferable embodiments, the inventive compositions will contain the active agents, including the inventive compound, in an amount effective to treat an indication of interest.
- the relative amounts of camptothecin compound and cyclodextrin may vary depending upon the intended use of the complex and the effect of the cyclodextrin on the camptothecin. Preferably, the ratio of the weight of camptothecin to the weight of cyclodextrin compound will be in a range between 1 :1 and 1 :5000.
- the circulating availability of the camptothecin will be significantly increased when the ratio of the weight of camptothecin to the weight of cyclodextrin compound is in a range between 1 :1 and 1 :2000. More preferably, the weight to weight ratio of camptothecin to cyclodextrin may be in a range of about 1 :5 to 1 :200 and even more preferably in a range of about 1 :5 to 1 :50.
- a pre- weighed amount of cyclodextrin compound which is preferably substantially pyrogen free is placed in a suitable depyrogenated sterile container.
- Methods for depyrogenation of containers and closure components are well known to those skilled in the art and are fully described in the United States Pharmacopeia 23 (United States Pharmacopeial Convention, Rockville, Maryland, USA).
- depyrogenation is accomplished by exposing the objects to be depyrogenated to temperatures above 400°C for a period of time sufficient to fully incinerate any organic matter. As measured in U.S. P.
- Bacterial Endotoxin Units the formulation might contain no more than about 10 Bacterial Endotoxin Units per gram of amorphous cyclodextrin.
- substantially pyrogen free is meant that the cyclodextrin contains less than about 10 U.S. P. bacterial endotoxin units per gram using the U.S. P. method. More preferably, the cyclodextrin will contain between 0.1 and 5 U.S. P. bacterial endotoxin units per mg, under conditions specified in the United States Pharmacopeia 23.
- amorphous cyclodextrin which is substantially pyrogen free, until the desired concentration of cyclodextrin is in solution.
- a pre- weighed amount of the camptothecin may be added with agitation and with additional standing if necessary until it dissolves. Excipients, if any are desired, may be added with or subsequent to adding the camptothecin.
- the solution may then be filtered through a sterile 0.2 micron filter into a sterile holding vessel and may be subsequently filled in sterile depyrogenated vials and is capped.
- a pharmaceutically acceptable preservative may be added to the solution comprising the complex of camptothecin and cyclodextrin prior to filtration, filling and capping, or alternatively, may be added sterilely after filtration. Additional discussion concerning preparing camptothecin/cyclodextrin compositions according to the invention may be found in V.J. Stella et al., Cyclodextrins: Their Future in Drug Formulation and Delivery. Pharm Res, 14(5):556-567 (1997); A.M.
- composition of matter according to the invention may be supplied as a dry powder or as a solution. If the composition of matter is to be injected into a subject it may be rendered sterile prior to injection. Accordingly, the composition of matter according to the invention may be supplied as a sterile cake, plug or powder or as a sterile lyophilized preparation in a sterile vial suitable for the addition of a sterile diluent, or as a sterile liquid solution in a sterile container.
- the composition of matter may be rendered sterile prior to such administration. Any of the several known means for rendering such pharmaceutical preparations sterile may be used so long as the active pharmaceutical compound is not inactivated and the complex with the amorphous cyclodextrin is not degraded.
- the active pharmaceutical compound is heat stable, the composition of matter according to the invention may be heat sterilized. If the cytotoxic compound is not heat- stable but is not photo degraded the composition may be sterilized by exposure to ultraviolet light or by ionizing radiation.
- the composition of matter if in a powder form may be gas sterilized using, for example, ethylene oxide gas.
- the composition of matter according to the invention may be filter-sterilized using a
- composition of matter is an aqueous liquid
- it may be filled in a sterile container and supplied as a sterile liquid ready for further dilution or injection neat.
- sterile liquids may be freeze-dried or lyophilized in a sterile container and capped.
- the components may be sterilized by any of the known methods appropriate to preserving the composition or the camptothecin or the cyclodextrin prior to mixing in water and may be mixed using sterile equipment and technique.
- the solution may be lyophilized in sterile containers and capped. Prior to use the lyophilized composition of matter may be reconstituted using sterile water for injection.
- the container closure system used for containing the formulation according to the invention may also be treated to remove or destroy pyrogenic substances by means known in the art prior to filling and further processing.
- the formulation according to the invention may be supplied as a dry lyophilized powder as mentioned above or as a sterile non pyrogenic aqueous solution in a sterile container closure system such as a stoppered vial suitable for puncturing with a sterile syringe and needle.
- composition according to the invention may be supplied as a sterile non pyrogenic aqueous solution in a sterile syringe or syringe and needle.
- a sterile solution or powder it may also include a pharmaceutically acceptable preservative.
- the composition according to the invention may also be included in other dosage forms in addition to those appropriate for parenteral administration.
- Such dosage forms may be in the form of aqueous suspensions, elixirs, or syrups suitable for oral administration, or compounded as a cream or ointment in a pharmaceutically acceptable topical base allowing the inventive camptothecins to be absorbed across the skin.
- the formulation according to the invention may be compounded in a lozenge or suppository suitable for trans mucosal absorption.
- Another therapeutically interesting route of administration or coadministration is local delivery.
- Local delivery of inhibitory amounts of inventive compounds and/or compositions can be by a variety of techniques and structures that administer the inventive compounds and/or compositions at or near a desired site. Examples of local delivery techniques and structures are not intended to be limiting but rather as illustrative of the techniques and structures available. Examples include local delivery catheters, site specific carriers, implants, direct injection, or direct applications.
- Local delivery by a catheter allows the administration of a inventive compounds and/or compositions directly to the desired site.
- Examples of local delivery using a balloon catheter are described in EP 383 492 A2 and U.S. Pat. No. 4,636,195 to Wolinsky. Additional examples of local, catheter-based techniques and structures are disclosed in U.S. Pat. No. 5,049,132 to Shaffer et al. and U.S. Pat No. 5,286,254 to Shapland et al.
- the catheter must be placed such that the inventive compositions can be delivered at or near the desired site. Dosages delivered through the catheter can vary, according to determinations made by one of skill, but often are in amounts effective to create a cytotoxic or cytostatic effect at the desired site.
- these total amounts are less than the total amounts for systemic administration of the inventive compositions, and are less than the maximum tolerated dose.
- the inventive compounds delivered through catheters preferably should be formulated to a viscosity that enables delivery through a small treatment catheter, and may be formulated with pharmaceutically acceptable additional ingredients (active and inactive).
- Local delivery by an implant describes the placement of a matrix that contains the inventive compositions into the desired site.
- the implant may be deposited by surgery or other means.
- the implanted matrix releases the inventive compositions by diffusion, chemical reaction, solvent activators, or other equivalent mechanisms. Examples are set forth in Lange, Science 249:1527-1533 (September, 1990). Often the implants may be in a form that releases the inventive compositions over time; these implants are termed time-release implants.
- biostable implants may have a rigid or semi-rigid support structure, with inventive composition delivery taking place through a coating or a porous support structure.
- Other implants may be made of a liquid that stiffens after being implanted or may be made of a gel.
- inventive composition present in or on the implant may be in an amount effective to treat cell proliferation generally, or a specific proliferation indication, such as the indications discussed herein.
- One example of local delivery of the inventive composition by an implant is use of a biostable or bioabsorbable plug or patch or similar geometry that can deliver the inventive composition once placed in or near the desired site.
- a biostable or bioabsorbable plug or patch or similar geometry that can deliver the inventive composition once placed in or near the desired site.
- An example of such implants can be found in U.S. Pat. No. 5,429,634 to Narciso, Jr.
- a particular application of use of an implant according to the invention is treatment of cell proliferation in tissue that is not highly vascularized, as discussed briefly above.
- tissue An example of such tissue is bone tissue.
- the difficulty in treating uncontrolled proliferative cell growth in bone tissue may be exemplified by the difficulties in treating bone tumors.
- Such tumors are typically refractory to treatment, in part because bone tissue is not highly vascularized.
- An implant in or near the proliferative site may potentially have localized cytotoxic or cytostatic effects with regard to the proliferative site. Therefore, in one embodiment, the invention may be used to treat bone tumors.
- Stents are designed to mechanically prevent the collapse and reocclusion of the coronary arteries. Incorporating an inventive composition into the stent may deliver the inventive composition directly to or near the proliferative site. Certain aspects of local delivery by such techniques and structures are described in Kohn, Pharmaceutical Technology (October, 1990). Stents may be coated with the inventive composition to be delivered. Examples of such techniques and structures may be found in U.S. Pat. Nos. 5,464,650 to Berg et al., 5,545,208 to Wolff et al., 5,649,977 to Campbell, 5,679,400 to Tuch, EP 0 716 836 to Tartaglia et al.
- the inventive composition loaded stent may be biorotable, i.e. designed to dissolve, thus releasing the inventive composition in or near the desired site, as disclosed in U.S. Pat. No. 5,527,337 to Stack et al.
- the present invention can be used with a wide variety of stent configurations, including, but not limited to shape memory alloy stents, expandable stents, and stents formed in situ.
- Amounts of the inventive composition delivered by the stent can vary, according to determinations made by one of skill, but preferably are in amounts effective to create a cytotoxic or cytostatic effect at the desired site. Preferably, these total amounts are less than the total amounts for systemic administration of the inventive composition, and are preferably less than the maximum tolerated dose. Appropriate release times can vary, but preferably should last from about 1 hour to about 6 months, most preferably from about 1 week to about 4 weeks. Formulations including the inventive composition for delivery of the agent via the stent can vary, as determinable by one of skill, according to the particular situation, and as generally taught herein.
- Another example is a delivery system in which a polymer that contains the inventive composition is injected into the target cells in liquid form. The polymer then cures to form the implant in situ.
- a polymer that contains the inventive composition is injected into the target cells in liquid form. The polymer then cures to form the implant in situ.
- Another example is the delivery of an inventive composition by polymeric endoluminal sealing.
- This technique and structure uses a catheter to apply a polymeric implant to the interior surface of the lumen.
- the inventive composition incorporated into the biodegradable polymer implant is thereby released at the desired site.
- Another example of this technique and structure is described in WO 90/01969 to Schindler.
- Another example of local delivery by an implant is by direct injection of vesicles or microparticulates into the desired site. These microparticulates may comprise substances such as proteins, lipids, carbohydrates or synthetic polymers. These microparticulates have the inventive composition incorporated throughout the microparticle or over the microparticle as a coating.
- Local delivery also includes the use of topical applications.
- An example of a local delivery by topical application is applying the inventive composition directly to an arterial bypass graft during a surgical procedure.
- Other equivalent examples will no doubt occur to one of skill in the art.
- kits may be used in the form of kits.
- the arrangement and construction of such kits is conventionally known to one of skill in the art.
- kits may include containers for containing the inventive compositions, and/or other apparatus for administering the inventive compositions.
- 20(S)-camptothecin is obtained from Sigma. Hydroxypropyl- ⁇ - cyclodextrin is obtained according to U.S. Sharma et al., Pharmaceutical and Physical Properties of Paclitaxel (Taxol) Complexes with Cyclodextrins, J. Pharm. Sci. 84:1223-30 (1995).
- a composition containing the 20(S)-camptothecin and the hydroxypropyl- ⁇ -cyclodextrin is formed using the procedures generally outlined in U.S. Sharma et al. The complex is then tested for stability according to the methods of U.S. Sharma et al., and for activity using the human tumor xenograph models outlined in B. C.
- 9-amino-camptothecin is produced from 20(S)-camptothecin, according to literature methods. Hydroxypropyl- ⁇ -cyclodextrin is obtained according to U.S. Sharma et al., Pharmaceutical and Physical Properties of Paclitaxel (Taxol) Complexes with Cyclodextrins. J. Pharm. Sci. 84:1223-30 (1995). A composition containing the 9-amino-camptothecin and the hydroxypropyl- ⁇ -cyclodextrin is formed using the procedures generally outlined in U.S. Sharma et al. The complex is then tested for stability according to the methods of U.S.
- 9-aminocamptothecin is produced from 20(S)camptothecin, according to literature methods.
- Dimethyl- ⁇ -cyclodextrin is obtained according to U.S. Sharma et al., Pharmaceutical and Physical Properties of Paclitaxel (Taxol) Complexes with Cyclodextrins, J. Pharm. Sci. 84:1223-30 (1995).
- a composition containing the 9-nitrocamptothecin and the dimethyl- ⁇ -cyclodextrin is formed using the procedures generally outlined in U.S. Sharma et al.
- the complex is then tested for stability according to the methods of U.S. Sharma et al., and for activity using the human tumor xenograph models outlined in B. C.
- 9-nitrocamptothecin is produced by nitrating 20(S)camptothecin, according to literature methods, ⁇ -cyclodextrin is obtained according to O. Bekers et al., 2',3'-Dideoxyinosine (ddl): Its Chemical Stability and Cyclodextrin Complexation in Agueous Media, J Pharm Biomed Anal, 11(6):489-493 (Jun 1993); O. Bekers et al., Effect of Cyclodextrins on the Chemical Stability of Mitomvcins in Alkaline Solution, J Pharm Biomed Anal, 9(10-12):1055-1060 (1991); O.
- Irinotecan (Camptothecin-11) is obtained according to Nagahiro
- Yoshida et al. article The complex is then tested for stability according to the methods generally outlined in the A. Yoshida et al. article, and for activity using the human tumor xenograph models outlined in B. C. Giovanella et al., Protocols for the Treatment of Human Tumor Xenografts with Camptothecins, 803 Annals of the New York Academy of Sciences 181 (1996), and Henry S. Friedman et al., Treatment of Central Nervous System Xenografts with Camptothecins, 803 Annals of the New York Academy of Sciences 210 (1996).
- Example 6 Example 6:
- Topotecan is obtained from Sigma. 2,3-dihydroxypropyl- ⁇ - cyclodextrin is obtained according to A. Yoshida et al., Some
- the complex is then tested for stability according to the methods generally outlined in the A. Yoshida et al. article, and for activity using the human tumor xenograph models outlined in B. C. Giovanella et al., Protocols for the Treatment of Human Tumor Xenografts with Camptothecins, 803 Annals of the New York Academy of Sciences 181 (1996), and Henry S. Friedman et al., Treatment of Central Nervous System Xenografts with Camptothecins, 803 Annals of the New York Academy of Sciences 210 (1996).
- 9-nitrocamptothecin is produced by nitrating 20(S)camptothecin, according to literature methods.
- a series of substituted beta- cyclodextrins are prepared, according to F. Hirayama, Development and Pharmaceutical Evaluation of Hydrophobic Cyclodextrin Derivatives as Modified-Release Drug Carriers. Yakugaku Zasshi, 113(6):425-437 (1993).
- Compositions including these beta-cyclodextrins and 9- nitrocamptothecin are formed using the procedures generally outlined in the Hirayama article. These complexes are then tested for stability according to the methods generally outlined in the Hirayama article, and for activity using the human tumor xenograph models outlined in B. C.
- 20(S)-camptothecin is obtained from Sigma.
- a series of substituted beta-cyclodextrins are prepared, according to F. Hirayama, Development and Pharmaceutical Evaluation of Hvdrophobic Cyclodextrin Derivatives as Modified-Release Drug Carriers, Yakugaku Zasshi, 113(6):425-437 (1993).
- Compositions including these beta- cyclodextrins and 20(S)-camptothecin are formed using the procedures generally outlined in the Hirayama article.
- Camptothecins 803 Annals of the New York Academy of Sciences 181 (1996), and Henry S. Friedman et al., Treatment of Central Nervous System Xenografts with Camptothecins, 803 Annals of the New York Academy of Sciences 210 (1996).
- Example 1 The complex obtained in Example 1 is prepared in a gelatin capsule oral dosage formulation.
- the composition is administered to a patient suffering from pancreatic adenocarcinoma, according to the protocol set forth in Ethan A. Natelson et al., Phase I Clinical and Pharmacological Studies of 20-(S)-Camptothecin and 20-(S)-9- Nitrocamptothecin and Anticancer Agents. 803 Annals of the New York Academy of Sciences 224 (1996).
- the amount of the composition administered is normalized to provide equivalent levels of 9- nitrocamptothecin to those set forth in the Natelson et al, article.
- the patient's condition is then monitored clinically for disease progression.
- compositions of 9-nitrocamptothecin and various cyclodextrins are prepared according to Example 8. Differing release rates are determined for 9-nitrocamptothecin based upon differing cyclodextrin structures using the methods generally set forth in F. Hirayama, Development and Pharmaceutical Evaluation of Hvdrophobic Cyclodextrin Derivatives as Modified-Release Drug Carriers, Yakugaku Zasshi, 113(6):425-437
- compositions having differing release times are obtained. These compositions are then individually compounded into tablets, and are administered orally to human volunteers. Blood samples are taken from the volunteers, and the amount of closed lactone and open lactone forms of the 9-nitrocamptothecin, together with release time, is determined.
- Example 1 The composition of Example 1 is prepared. This composition is then used to prepare a coated stent, using the general teachings of Berg et al. (U.S. Pat. Nos. 5,464,650). A stenotic lesion is then induced in a conventional animal model, namely a pig artery. The nature and dimensions of the stenotic lesion are then determined using a catheter and an appropriate viewing device. The stent is then deployed at the lesion site, using a conventional stent deployment catheter and balloon. After one week, the pig is sacrificed, and the degree of restenotic growth is determined. This amount of growth is compared against a control animal where the deployed stent is not coated.
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Abstract
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US539982 | 1990-06-18 | ||
US53998200A | 2000-03-31 | 2000-03-31 | |
PCT/US2001/006829 WO2001074401A2 (fr) | 2000-03-31 | 2001-03-02 | Complexes de camptothecine |
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US7071202B2 (en) * | 2002-02-21 | 2006-07-04 | Supergen, Inc. | Compositions and formulations of 9-nitrocamptothecin polymorphs and methods of use therefor |
EP1534340B1 (fr) * | 2002-09-06 | 2011-11-16 | Cerulean Pharma Inc. | Polymeres a base de cyclodextrine pour l'administration de medicaments lies par liaison covalente |
EP2153821A1 (fr) * | 2008-08-06 | 2010-02-17 | BioAlliance Pharma | Formules orales de dérivés de camptothécine |
US20110207760A1 (en) * | 2010-02-23 | 2011-08-25 | Valery Alakhov | Sn-38 compositions |
US9422303B2 (en) | 2010-10-29 | 2016-08-23 | Health Research, Inc. | Formulations of water-insoluble chemical compounds and methods of using a formulation of compound FL118 for cancer therapy |
WO2014055493A1 (fr) | 2012-10-02 | 2014-04-10 | Cerulean Pharma Inc. | Procédés et systèmes s'appliquant à la précipitation de polymères et à la génération de particules |
CN105561406A (zh) * | 2016-02-15 | 2016-05-11 | 丹阳纳瑞康纳米科技有限公司 | 一种含复合药物涂层的血管支架 |
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US5464650A (en) * | 1993-04-26 | 1995-11-07 | Medtronic, Inc. | Intravascular stent and method |
US6495579B1 (en) * | 1996-12-02 | 2002-12-17 | Angiotech Pharmaceuticals, Inc. | Method for treating multiple sclerosis |
US6485514B1 (en) * | 1997-12-12 | 2002-11-26 | Supergen, Inc. | Local delivery of therapeutic agents |
US6048736A (en) * | 1998-04-29 | 2000-04-11 | Kosak; Kenneth M. | Cyclodextrin polymers for carrying and releasing drugs |
JP2002519335A (ja) * | 1998-06-26 | 2002-07-02 | クアナム メディカル コーポレイション | 再狭窄の予防のためのトポイソメラーゼインヒビター |
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2001
- 2001-03-02 EP EP01914662A patent/EP1267936A2/fr not_active Withdrawn
- 2001-03-02 WO PCT/US2001/006829 patent/WO2001074401A2/fr active Application Filing
- 2001-03-02 AU AU2001240024A patent/AU2001240024A1/en not_active Abandoned
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