Title:  Gel delivery vehicles for anticellular proliferative agents

United States Patent:  6,630,168

Issued:  October 7, 2003

Inventors:  Jones; Richard E. (Palo Alto, CA); Washco; Keith (Fremont, CA); Roskos; Kathleen V. (Los Altos, CA); Maskiewicz; Richard (Sunnyvale, CA); Trager; George (San Mateo, CA)

Assignee:  BioMedicines, Inc. (Emeryville, CA)

Appl. No.:  803128

Filed:  February 20, 1997

Abstract

Methods and compositions are provided for the treatment of a host suffering from a cellular proliferative disease. In the subject methods, antiproliferative agents are administered in a substantially non-aqueous gel delivery vehicle comprising at least one polar organic solvent in combination with one or more thickening agents. The subject methods and compositions provide for the enhanced efficacy of regionally or locally administered antiproliferative proliferative agents.

SUMMARY OF THE INVENTION

Methods and compositions are provided for the treatment of a host with a cellular proliferative disease, wherein at least one antiproliferative agent is administered to the host in a substantially non-aqueous, gel delivery vehicle capable of enhancing the efficiency of the agent. The vehicles employed in the subject invention are pharmaceutically acceptable and comprise at least one polar organic solvent in combination with at least one thickening agent. The subject methods and compositions find use in the treatment of a variety of cellular proliferative diseases, where the subject methods result in at least enhanced efficacy of the administered agent.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Methods and compositions are provided for the treatment of a host suffering from a cellular proliferative disease. In the subject methods, substantially non-aqueous gel delivery vehicles are employed for the regional or local administration of one or more antiproliferative agents. The substantially non-aqueous gel delivery vehicles are pharmaceutically acceptable and comprise at least one polar organic solvent in combination with at least one thickening agent. The subject methods and compositions find use in the treatment of a variety of cellular proliferative diseases, and provide for at least enhanced efficacy of the delivered agent.

Critical to the subject methods is the use of an substantially non-aqueous gel vehicle for delivery of the antiproliferative agent. The vehicle formulations are pharmaceutically acceptable when used in accordance with the subject methods. By "substantially non-aqueous" is meant that these vehicles contain no more than about 30% water. More preferably, they will comprise less than about 5% (v/v) water, usually less than about 3% (v/v) water, more usually less than about 1% (v/v) water, preferably less than about 0.5% (v/v) water.

The substantially non-aqueous delivery vehicles employed in the subject methods are capable of acting as a depot for one or more cellular antiproliferative agents. As the subject delivery vehicles act as a depot for the agent(s), the dispersion of the agent(s) from the vehicle and site of administration will be retarded or slowed as compared to the dispersion of the agent when delivered in a saline solution.

The delivery vehicles have gel-like consistencies but are sufficiently flowable so as to be capable of local or regional administration through a catheter, needle, or other comparable means of local or regional administration. Generally, the subject vehicles will have a viscosity ranging from about 500 to 50,000 mPa.multidot.sec, usually from about 1,000 to 40,000 mPa.multidot.sec, and more usually from about 2,000 to 30,000 mPa.multidot.sec, all at a shear rate of 10 sec^-1.

The gel vehicles of the subject invention will comprise at least one polar organic solvent, where two or more different polar organic solvents may be present in the formulation, usually not more than four polar organic solvents, more usually not more than three polar organic solvents. The organic solvent component will make up the majority of the vehicle formulation and provide for a continuous fluid phase, with the organic solvent component ranging from about 65 to 98% (v/v) of the formulation, usually from about 80 to 98% (v/v) of the formulation, more usually from about 90 to 95% (v/v) of the vehicle formulation, most preferably from about 75 or 80% to 99.5% (v/v).

Polar organic solvents that find use in the subject invention are not excessively toxic at the dosage levels at which, as well as the manner in which, they are administered, where "not excessively toxic" intends that the solvents in the subject vehicles do not result in unacceptable systemic toxicity when administered in accordance with the subject invention. Polar organic solvents of interest will be at least somewhat water soluble, having a Hildebrand Solubility Parameter of at least about 7.5 or 8 (Cal/cc)^1/2, usually at least about 9, more usually at least about 10. The solvents will have dipole moments of at least about 1.5 D, usually at least about 2.0 D.

The polar organic solvents may comprise C, N, O, S, H and P, and may be cyclic, usually heterocyclic, and will generally be of low molecular weight, having a molecular weight of greater than about 30 Da, usually greater than about 40 Da, but less than about 500 Da, usually less than about 275 Da and more usually less than about 250 Da. The solvents will generally have from 1 to 12 carbon atoms, usually from 2 to 10 carbon atoms, and more usually from 2 to 8 carbon atoms, and will comprise one or more heteroatoms, typically no more than 8 heteroatoms, usually no more than 6 heteroatoms, and more usually fewer than 4 heteroatoms.

Organic solvents of interest will comprise 1 or more oxygen containing substituent groups, usually no more than 4 oxygen containing substituents, more usually no more than 3 oxygen containing substituents, where oxygen containing substituents include oxy, oxo and acid groups, both organic (e.g carboxy) and inorganic, e.g. sulphur or phosphorus, and the like, where particular substituent groups of interest include: amides and ureas; esters, e.g. carboxylic esters, carbonate esters; ethers; hydroxy groups, and the like. Preferred oxo substituents include amides, esters, acetals and sulfoxides.

Solvents comprising hydroxy substituents include lower alkanols of from 2 to 4 carbon atoms and 1 to 3 hydroxy groups, usually having no more than 1 hydroxy group for every 1.5 carbon atoms. Lower alkanols of interest include ethanol, 1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol, glycerol, 2-methyl-2-propanol, and the like, with ethanol being preferred.

Amides of interest may be cyclic and include both N-substituted and unsubstituted amides, where any N-substituents will usually be alkyls of from 1 to 4 carbon atoms, more usually 1 to 3 carbon atoms. Particular amides of interest include: formamide, methyl formamide, dimethyl formamide, ethyl formamide, diethyl formamide, acetamide, methyl acetamide, dimethyl acetamide, ethyl acetamide, diethyl acetamide. Cyclic amides (lactams) of interest include 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone. Ureas of interest include tetramethyl urea, 1,3-dimethyl-2-imidazolidinone, and the like.

Esters of interest include esters of carboxylic acids as well as esters of inorganic acids. Examples of the former include triacetin, triethyl citrate, ethyl lactate, and the like. Examples of the latter include carbonate esters, where particular carbonate esters include: propylene carbonate, 1,2-butylene carbonate, 2,3-butylene carbonate and the like, with propylene carbonate being referred. Other solvents of interest finding use in the subject vehicles include dimethyl sulfoxide, diethyl sulfoxide, hexamethyl phosphoramide, pyruvic aldehyde dimethylacetal, dimethylisosorbide and the like.

In the subject vehicle formulations, in combination with the polar organic solvent component will be at least one thickening or gelling agent, where a plurality of thickening agents may be employed, usually not more than 3 different thickening agents, more usually not more than 2 different thickening agents. Thickening agents finding use in the subject vehicles will be those agents capable of substantially increasing the viscosity of the formulation to provide for a vehicle having a viscosity ranging from about 500 to 50,000 mPa.multidot.sec, usually from about 1,000 to 40,000 mPa.multidot.sec, and more usually from about 2,000 to 30,000 mPa.multidot.sec all at a shear rate of 10 sect^-1. Generally, the thickening agent component of the formulation will range from about 0.5 to 20% (v/v) of the formulation, usually from about 1 to 15% (v/v) of the formulation, more usually from about 2 to 10% (v/v) of the formulation.

Thickening agents of interest, also known as viscosity enhancing agents, are pharmaceutically acceptable for parenteral use when employed in the subject formulations. Finding use as thickening agents in the subject vehicles are fatty acids and other fatty acid esters, as well as the aluminum and magnesium salts thereof, and biocompatible polymers. Fatty acids that find use as thickening agents in the subject vehicles will generally be naturally occurring fatty acids having 12 to 20 carbon atoms, usually 14 to 18 carbon atoms, where the fatty acids may be saturated or have one or more sites of ethylenic unsaturation, usually not more than 4 sites of unsaturation, more usually not more than 2 sites of unsaturation, where monounsaturated fatty acids are preferred. Specific fatty acids of interest include lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, and the like, particularly oleic acid. Also of interest as thickening agents are the aluminum and magnesium salts of the above fatty acids, usually aluminum salts of the above fatty acids, particularly aluminum monostearate.

Thickening agents of interest also include biocompatible synthetic, naturally occurring or modified naturally occurring polymers capable of imparting the desired viscosity to the delivery vehicles. Polymers finding use as thickening agents in the subject vehicles may be non-crosslinked or where the polymers may be linear or branched, but will usually be linear. Polymers of interest may be homo- or copolymers, where the copolymers may be random or block copolymers, and include proteins such as collagen or gelatin, polysaccharides, polyoxyalkylenes, polyvinyls, and the like.

Polysaccharides finding use may be either naturally occurring or chemically modified versions thereof, particularly modified celluloses, where the modified celluloses will have molecular weights ranging from about 5,000 to 200,000 Da, usually from about 10,000 to 150,000 Da, where the cellulosic backbone may be modified with a variety of different pendant groups, including alkyl groups of from 1 to 4 carbon atoms, usually 1 to 2 carbon atoms, hydroxyalkyl groups of from 2 to 4 carbon atoms, carboxyalkyl groups of from 2 to 4 carbon atoms, and the like. Specific modified celluloses of interest include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose and the like.

Polyoxyalkylenes of interest include high molecular weight polyoxyethylene compounds, where the compounds may be homopolymers, e.g. polyethylene glycols, or copolymers of oxyethylene and oxypropylene monomeric units, e.g. poloxamers. High molecular weight polyoxyalkylene compounds finding use as thickening agents in the subject invention will generally have a molecular weight of at least about 5,000 Da, usually at least about 7,000 Da, and may be as high as 50,000 Da or higher, but will usually be less than 20,000 Da. For polyoxyalkylene copolymers, the copolymers will generally be block copolymers of polyoxyethylene and polyoxypropylene units, where the polyoxyethylene units will generally range from about 20 to 90% by weight of the polymer.

Other polymers of interest include polyvinyl polymers, such as carboxypolymethylene (carbomer), polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and the like. Polyvinyl polymers of particular interest include carboxypolymethylene (carbomer), polyvinylpyrolidones (povidones) having molecular weights ranging from about 50,000 to about 500,000 Da.

Of particular interest as substantially non-aqueous delivery vehicles are the following solvent and thickening agent combinations: (1) ethanol thickened with hydroxypropyl cellulose in combination with oleic acid; (2) dimethylacetamide thickened with methyl cellulose, hydroxypropylmethyl cellulose, or carboxypolymethylene; and (3) propylene carbonate thickened with polyvinylpyrrolidone.

In addition to the polar organic solvent and thickening agent components, the delivery vehicle formulations may further comprise various modifying agents that increase the stability and/or usefulness of the final formulation, where such agents include antibacterial and antimicrobial preservatives, buffers, antioxidants, and other pharmaceutical adjuvants. Antibacterial and microbial agents finding use include benzoic acid, butyl paraben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylmercuric nitrate, thimerosol, and the like. Antioxidants finding use include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite and the like. Buffering agents of interest include potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium citrate anhydrous, sodium citrate dihydrate, and the like. These additional agents, when present, will be no more than about 5% (v/v) of the vehicle formulation, usually no more than about 3% (v/v) of the vehicle formulation, more usually no more 2% (v/v) of the formulation.

Also present in the subject vehicle formulations may be various effector agents which further enhance the efficacy of the anticellular proliferative agents delivered in the vehicle formulation. Effector agents of particular interest include vasomodulators, immune modulators, etc. which are used to affect host responsiveness. Of particular interest are effectors which restrict regional vasculature, e.g. vasoactive agents, either as to growth and/or passage opening, e.g. vasoconstrictive or sympathomimetic agents. These effectors include catechol amines, e.g. epinephrine and its borate salt, nor-epinephrine, dipivefrin, ephedrine, ergot alkaloids, prostaglandins, angiotensin, and the like. When present in the subject formulation, these effector agents will be at least about 0.005% (w/v) of the formulation, usually at least about 0.01% (v/v) of the formulation and less than about 0.1% (w/v) of the formulation, usually less than about 0.05% (v/v) of the formulation.

The subject vehicle formulations find use in the delivery of a wide variety of antiproliferative agents, where antiproliferative or cytostatic agents of interest are agents that tend to retard cellular activity and multiplication, and are preferably cytotoxic. The subject vehicle formulations may be used to deliver one or a combination of agents, where when a combination of agents are delivered in the subject vehicles, the combination will usually consist of no more than 3 agents, more usually no more than 2 agents. In the antiproliferative composition comprising both the antiproliferative agent and vehicle, the agent will be homogeneously distributed throughout the vehicle formulation, where the agent may be present in solution or as a dispersion, e.g. a coarse dispersion, such as a suspension or emulsion, or a fine dispersion such as a colloidal dispersion, including magmas and gels. The antiproliferative agent will be present in the subject vehicle formulation in amounts ranging from about 0.01 to 100 mg/mL of vehicle formulation, usually from about 0.02 to 50 mg/mL, more usually from about 0.1 to 50 mg/mL of the formulation, depending on the particular agent and delivery vehicle.

Antiproliferative agents of interest include antimetabolites, covalent and non-covalent DNA binding agents, chromatin function inhibiting agents, endocrine function inhibiting agents, naturally occurring antiproliferative agents and derivatives thereof, and the like. Antimetabolites of interest include: folate antagonists, e.g. methotrexate (MTX, amethopterin), trimetrexate (TMQ); pyrimidine antagonists, e.g. fluorouracil (5-FU), flurodeoxyuridine (FUDR), CB3717, azacytidine (Aza-C, 5-AC); purine antagonists, e.g. mercaptopurine (MP, 6-MP), thioguanine (TG, 6-TG), tiazofuirin, chlorodeoxyadenosine (CdA), pentostatin (2'-deoxycoformycin, dCF); sugar modified analogs, e.g. cytarabine (ara-C), fludarabine (F-ara-A); ribonucleotide reductase inhibitors, e.g hydroxyurea (HU); and the like. Covalent DNA-binding agents include: nitrogen mustards, e.g. mechlorethamine (HN2, nitrogen mustard), chlorambucil, melphalan (L-phenylalanine mustard, L-PAM), cyclophosphamide, ifosfamide; aziridines, e.g. thiotepa, altretamine (hexamethylmelamine), mitomycin (mitomycin C); alkane sulfonates, e.g. busulfan, nitrosoureas, e.g carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozotocin; platinum compounds, e.g cisplatin (cis-DDP), carboplatin; methylating agents, e.g dacarbazine, procarbazine; and the like. Hypoxia selective cytotoxics include porfiromycin, nitracrine, nitracrine N-oxide, and diynene such as neocarzinostatin and dynemicin; and the like. Non-covalent DNA-binding or DNA intercalating agents include: anthracyclines, e.g. daunorubicin, doxorubicin, idarubicin; mitoxantrone; dactinomycin; bleomycin; plicamycin; and the like. Chromatin fumction inhibitors include: topoisomerase inhibitors, e.g. epipodophyllotoxins such as etoposide (VP-16) and teniposide (VM-26), amsacrine (m-AMSA), camptothecin (CFT), topotecan (TPT), irinotecan (CPT-11) and other campothecin derivatives; microtubule inhibitors, e.g. vinca alkaloids such as vinblastine, vincristine and vindesine, paclitaxel (taxol); and the like. Endocrine function affecting agents include: glucocorticoids, e.g. prednisone, prednisolone; estrogens, e.g. diethylstilbestrol (DES), ethinyl estradiol; antiestrogens, e.g. tamoxifen; progestins, e.g. medroxyprogesterone, megestrol; androgens, e.g. fluoxymestrone, testosteron; antiandrogens, e.g. cyproterone acetate, flutamide; LHRH (GNRH) agonists, e.g. goserelin, leuprolide; aromatase inhibitors, e.g. aminoglutethimide; adrenocortical suppressors, e.g. mitotane (o,p'-DDD); and the like. Naturally occurring antiproliferative agents include: interferons, (e.g. .gamma., .gamma.-1a, .beta., .alpha., etc.), interleukins (e.g. 2, 4, and 10), TNF-.alpha. and -.beta., and the like.

The subject antiproliferative compositions may be prepared using conventional methods, where the resultant preparations will generally be sterile and nonpyrogenic.

The antiproliferative compositions having been described, their use in the treatment of a host with a cellular proliferative disease will now be discussed in greater detail. The subject compositions find particular use in the treatment of hosts with cellular proliferative diseases characterized by lesions or solid tumors, such as neoplastic diseases. In the subject methods, the antiproliferative compositions are regionally or locally administered. Thus, the antiproliferative compositions are administered at least proximally to a target site of the host, where "target site" is defined as a location of a lesion associated with the cellular proliferative disease afflicting the host, e.g. a tumor. By "at least proximally" is meant that the composition is administered in apposition to the lesion, such that the dispersion of antiproliferative agent from the composition is localized to the region of the lesion, whereby the concentration of antiproliferative agent in the region of the lesion, as well as in the lesion itself, is significantly greater than the systemic concentration of the agent. Where the composition is administered locally, it will be administered directly at the site of a lesion of cellular proliferative disease, usually intralesionally or intratumorally. Convenient methods of regional or local administration include administration via syringe needle, catheter, trochar, and the like.

Therapies which employ the subject compositions and methods may vary depending on the particular host, the nature of the cellular proliferative disease, the size of the lesion and the like. Thus, the antiproliferative composition may be administered once in a particular therapy, where therapy intends the entire course of treatment of the host, or several times, where the interval between administrations may be a matter of hours, days, or even months.

In the subject methods, the volume of distribution, concentration distribution and total dosage of agent(s) in the composition administered to the host are controlled by varying the compositions and/or the method of administration. This is especially important when using drugs with high toxicity, limited stability in vivo, high cost, etc. As indicated above, the drug concentration, vehicle formulation selection and additives may be varied in relation to the particular indication, host condition, growth stage of the tumor, etc. In addition, the previously mentioned parameters are influenced by providing a single injection or multiple injections into separate regions of the tumor, by controlling the localized temperature and blood circulation at the site of administration to reduce systemic dispersion of the agent, and the like. Generally, the volume and concentration of the subject compositions administered at least proximal to the lesion mass should be sufficient to contact as many abnormal cells as possible with a lethal dosage of agent while minimizing exposure to and/or necrosis of surrounding and/or sensitive normal tissue. The volume of composition administered to the tumor in a particular administration may range from 1 to 100 .mu.L, usually 10 to 50 .mu.L per 100 mm³ of treated tissue. The dose of cytostatic agent delivered to a tumor site in a particular administration may range from about 0.01 to 200 mg/kg of host, and will usually range from about 0.1 to 100 mg/kg of host, substantially varying with the particular agent, the nature of the composition and tumor, the host and the like.

Although the effector agents described above may be included within the subject compositions for simultaneous administration, the effectors may also be administered shortly before or after the subject compositions. When the effector agent is administered after administration of the composition, the effector agent will be administered within about 8 hours, preferably within about 4 hours, more preferably within about 2 hours, and most preferably within about 1 hour. Where the effector agent is administered before the subject composition, e.g. in instances where it may be advantageous to "prime" the host with an effector agent, e.g. epinephrine, administration will usually be within about 60 minutes, preferably within about 10 minutes, more preferably within about 2 minutes prior to the administration of the subject compositions.

The subject methods may be used to treat a wide variety of hosts, including mammalian hosts, such as domestic animals, e.g. pets and livestock, rare or exotic animals, and humans. Cellular proliferative diseases amenable to treatment with the subject formulations are diseases characterized by the abnormal proliferation of cells. Diseases characterized by the abnormal proliferation of cells include neoplasia, psoriasis, hyperplasia and the like.

Neoplastic diseases amenable to treatment according to the subject methods include neoplastic diseases characterized by the development of solid tumors or lesions, including solid malignant tumors of the lung, breast, colon, rectum, ovaries, stomach, pancreas, uterus, testicles, brain, liver, head and neck, prostate and the like. Typically, therapeutic gain can be realized with tumors greater than about 50 mm³, particularly with tumors greater than 100 mm³, and more particularly with tumors greater than 200 mm³. Particular neoplastic cellular proliferative diseases that may be treated with the subject methods include carcinomas, sarcomas and melanomas, such as basal cell carcinoma, squamous cell carcinoma, melanoma, soft tissue sarcoma, solar keratoses, Kaposi's sarcoma, cutaneous malignant lymphoma, Bowen's disease, Wilm's tumor, hepatomas, colorectal cancer, brain tumors, mycosis fungoides, Hodgkins lymphoma, polycythemia Vera, lymphomas, oat cell sarcoma, superficial and invasive bladder tumors, ovarian cancer, etc.

The effectiveness of the disclosed methods may generally be characterized as reducing the severity of toxicity to tissue surrounding the lesion and reducing tumor burden, reducing host systemic toxicity to the presence of the antiproliferative agent, as well as delaying growth and tumor progression. The disclosed methods generally result in an inhibition in the growth of the proliferative lesion as compared with no treatment, systemic treatment or intralesional treatment with the delivered drug in an aqueous or predominantly aqueous vehicle (i.e., water in an amount in excess of 50%).

Also provided are kits comprising the gel vehicle composition separate from the antiproliferative agent(s), where such kits find use when it is preferable to prepare the formulation immediately prior to use. In addition to the vehicle and antiproliferative agent(s), the kits may further comprise mixing means for preparing the final antiproliferative composition to be administered. For example, the vehicle may be provided in a first container and the active agent(s) in a second container, where the kit comprises a means for combining the vehicle and agent into the final antiproliferative composition, e.g. a mixing adapter where the agent and vehicle are present in separate syringes.

Claim 1 of 1 Claim

What is claimed is:

1. A method for treating a host suffering from a neoplastic disease, said method comprising:

intralesionally administering to said host a composition comprising an antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising dimethylacetamide in combination with methyl cellulose, hydroxypropyl methylcellulose, or carboxypolymethylene;

wherein said substantially non-aqueous delivery vehicle has a gel-like consistency with a viscosity ranging from about 500 to 50.000 mPa.multidot.sec and does not solidify upon contact with an aqueous environment.

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