Compositions and dosage forms for gasteric delivery of antineoplastic agents and methods of treatment that use them to inhibit cancer cell proliferation

Abstract

The present invention provides oral dosage forms and compositions for administering antineoplastic agents, such as irinotecan, etoposide, paclitaxel, doxorubicin and vincristine, whose oral effectiveness is limited by pre-systemic and systemic deactivation in the GI tract. Gelling of the gastric retention vehicle composition, and in the case of solid forms concomitant expansion of the composition, retains the antineoplastic drug in the patient's stomach, minimizing pre-systemic and/or systemic deactivation of the drug.

1 .- 3 . (Canceled)  
     
     
         4 . A method of inhibiting cell proliferation in a tumor of a patient by orally administering a gastric retention solid dosage form or liquid composition containing an antineoplastic agent that is susceptible to removal by the P-glycoprotein efflux pump, 
 wherein the dosage form or liquid composition releases the antineoplastic agent in the patient's stomach,    wherein the biovailability of the antineoplastic agent is greater than the bioavailability when the antineoplastic agent is administered in a non-gastric retention solid dosage form or liquid composition, resulting in enhanced systemic delivery of the antineoplastic agent to the tumor.    
     
     
         5 . The method of  claim 4  wherein bioavailability is measured by the area under a curve of bloodstream concentration of the antineoplastic agent versus time.  
     
     
         6 . The method of  claim 4  wherein the antineoplastic agent is selected from the group consisting of etoposide, paclitaxel, doxorubicin and vincristine.  
     
     
         7 . (Canceled)  
     
     
         8 . A solid pharmaceutical dosage form for enhanced systemic delivery of an antineoplastic agent comprising, as an active ingredient, an antineoplastic agent wherein the antineoplastic agent is absorbable through the lining of the stomach, jejunum or duodenum of a patient and a gastric retention vehicle composition comprising a hydrogel, wherein the dosage form expands upon contact with gastric fluid and wherein after ingestion by a patient the gastric retention vehicle composition expands to retain the dosage form in the patient's stomach for a prolonged period of time and wherein the active ingredient is susceptible to base induced deactivation.  
     
     
         9 . The pharmaceutical dosage form of  claim 8  wherein the antineoplastic agent is irinotecan.  
     
     
         10 - 12 . (Canceled).  
     
     
         13 . The pharmaceutical dosage form of  claim 8  wherein the antineoplastic agent is susceptible to deactivation by the Pgp efflux pump of cells of the lining of the small intestine.  
     
     
         14 . The pharmaceutical dosage form of  claim 13  wherein the antineoplastic agent is selected from the group consisting of etoposide, paclitaxel, doxorubicin and vincristine.  
     
     
         15 . The solid pharmaceutical dosage form of  claim 14  wherein the antineoplastic agent is etoposide.  
     
     
         16 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with testicular tumors by orally administering a dosage form of  claim 15  to the patient.  
     
     
         17 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with testicular tumors by executing a therapeutic program of repeated oral administration of dosage forms of  claim 15  to the patient.  
     
     
         18 . The method of  claim 17  wherein the dosage forms contain a unit dose of from about 25 to about 250 milligrams of etoposide.  
     
     
         19 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with small cell lung cancer by orally administering a dosage form of  claim 15  to the patient.  
     
     
         20 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with small cell lung cancer by executing a therapeutic program of repeated oral administration of dosage forms of  claim 15  to the patient.  
     
     
         21 . The method of  claim 20  wherein the dosage forms contain a unit dose of from about 25 to about 250 milligrams of etoposide.  
     
     
         22 . The solid pharmaceutical dosage form of  claim 14  wherein the antineoplastic agent is paclitaxel.  
     
     
         23 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with non-small cell lung cancer by orally administering a dosage form of  claim 22  to the patient.  
     
     
         24 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with non-small cell lung cancer by executing a therapeutic program of repeated oral administration of dosage forms of  claim 22  to the patient.  
     
     
         25 . The method of  claim 24  wherein the dosage forms contain a unit dose of from about 25 to about 250 milligrams of paclitaxel.  
     
     
         26 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with ovarian cancer by orally administering a dosage form of  claim 22  to the patient.  
     
     
         27 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with ovarian cancer by executing a therapeutic program of repeated oral administration of dosage forms of  claim 22  to the patient.  
     
     
         28 . The method of  claim 27  wherein the dosage forms contain a unit dose of from about 25 to about 250 milligrams of paclitaxel.  
     
     
         29 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with breast cancer by orally administering a dosage form of  claim 22  to the patient.  
     
     
         30 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with breast cancer by executing a therapeutic program of repeated oral administration of dosage forms of  claim 22  to the patient.  
     
     
         31 . The method of  claim 30  wherein the dosage forms contain a unit dose of from about 25 to about 250 milligrams of paclitaxel.  
     
     
         32 .- 50 . (Canceled).  
     
     
         51 . A liquid pharmaceutical composition for enhanced systemic delivery of antineoplastic agents comprising, as an active ingredient, an antineoplastic agent that is capable of absorption through the lining of the stomach, jejunum or duodenum of a patient and a gastric retention vehicle composition comprising a gelling agent wherein after ingestion by the patient the gastric retention vehicle composition gels or precipitates to retain the dosage form in the patient's stomach for a period of three hours or more.  
     
     
         52 . The liquid pharmaceutical composition of  claim 51  wherein the gastric retention vehicle composition comprises a protein.  
     
     
         53 . The liquid pharmaceutical composition of  claim 52  wherein the protein is selected from the group consisting of serum albumin, oval albumin, casein and gelatin.  
     
     
         54 . The liquid pharmaceutical composition of  claim 51  wherein the gastric retention vehicle composition comprises a polysaccharide.  
     
     
         55 . The liquid pharmaceutical composition of  claim 54  wherein the gastric retention vehicle composition comprises a mixture of ethylhydroxyethylcellulose and a surfactant selected from the group consisting of cationic surfactants or anionic surfactants that are not extensively protonated in gastric fluid.  
     
     
         56 . The liquid pharmaceutical composition of  claim 55  wherein the surfactant is selected from the group consisting of hexadecyltrimethylammonium chloride, tetradecylbetainate chloride and hexadecylpyridinium chloride, sodium dodecyl sulfate, sodium dodecyl monoethyleneoxide sulfate, sodium dodecyl sulfonate, sodium dosdecyl phosphate, sodium dodecyl phosphonate and sodium p-dodecylbenzene sulfonate.  
     
     
         57 . The liquid pharmaceutical composition of  claim 54  wherein the gastric retention vehicle composition comprises low methoxylated pectin and a divalent metal salt.  
     
     
         58 . The liquid pharmaceutical composition of  claim 57  wherein the low methoxylated pectin has a 20-50 percent degree of methoxylation and a 3-23% degree of amidation.  
     
     
         59 . The liquid pharmaceutical composition of  claim 57  wherein the divalent metal salt is calcium carbonate.  
     
     
         60 . The liquid pharmaceutical composition of  claim 54  wherein the gastric retention vehicle composition comprises methylcellulose.  
     
     
         61 . The liquid pharmaceutical composition of  claim 60  wherein the methylcellulose comprises 5% or more of the dosage form by weight.  
     
     
         62 . The liquid pharmaceutical composition of  claim 51  wherein the gastric retention vehicle composition comprises a mixture of from about 0.5 weight percent sodium alginate, from about 0.5 to about 3 weight percent of a natural polymer selected from the group consisting of xanthan gum, carrageenan and gelatin.  
     
     
         63 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with meta-static carcinoma of the colon or rectum by orally administering a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is irinotecan.  
     
     
         64 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with meta-static carcinoma of the colon or rectum by executing a therapeutic program of repeated oral administration of a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is irinotecan.  
     
     
         65 . The method of  claim 64  wherein the liquid pharmaceutical composition is administered in a unit dose of from about 20 to about 250 milligrams of irinotecan.  
     
     
         66 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with testicular tumors by orally administering a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is etoposide.  
     
     
         67 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with testicular tumors by executing a therapeutic program of repeated oral administration of a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is etoposide.  
     
     
         68 . The method of  claim 67  wherein the liquid pharmaceutical composition is administered in a unit dose of from about 25 to about 250 milligrams of etoposide.  
     
     
         69 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with small cell lung cancer by orally administering a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is etoposide.  
     
     
         70 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with small cell lung cancer by executing a therapeutic program of repeated oral administration of a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is etoposide.  
     
     
         71 . The method of  claim 70  wherein the liquid pharmaceutical composition is administered in a unit dose of from about 25 to about 250 milligrams of etoposide.  
     
     
         72 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with ovarian cancer by orally administering a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is paclitaxel.  
     
     
         73 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with ovarian cancer by executing a therapeutic program of repeated oral administration of a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is paclitaxel.  
     
     
         74 . The method of  claim 73  wherein the liquid pharmaceutical composition is administered in a unit dose of from about 25 to about 250 milligrams of paclitaxel.  
     
     
         75 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with breast cancer by orally administering a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is paclitaxel.  
     
     
         76 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with breast cancer by executing a therapeutic program of repeated oral administration of a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is paclitaxel.  
     
     
         77 . The method of  claim 76  wherein the liquid pharmaceutical composition is administered in a unit dose of from about 25 to about 250 milligrams of paclitaxel.  
     
     
         78 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with non-small cell lung cancer by orally administering a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is paclitaxel.  
     
     
         79 . A method of inhibiting cell proliferation in a tumor of a patient afflicted with non-small cell lung cancer by executing a therapeutic program of repeated oral administration of a liquid pharmaceutical composition of  claim 51  wherein the antineoplastic agent is paclitaxel.