Absorption enhancers for drug administration

Abstract

A composition including a surfactant and at least one alkyl glycoside and/or saccharide alkyl ester and a drug. The surfactant composition(s) when admixed with a drug is non-toxic and non-irritating, while stabilizing and increasing the bioavailability of the drug. The invention also provides compositions that enhance absorption of drugs via the oral, ocular, nasal, nasolacrimal, inhalation or pulmonary, oral cavity (sublingual or Buccal cell) or CSF delivery route of a patient, including but not limited to insulin, glucagon and exendin-4.

1 - 86 . (canceled)  
   
   
       87 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of Exenatide in a pharmaceutically acceptable carrier.  
   
   
       88 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of GLP-1 in a pharmaceutically acceptable carrier.  
   
   
       89 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of nicotine in a pharmaceutically acceptable carrier.  
   
   
       90 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of interferon in a pharmaceutically acceptable carrier.  
   
   
       91 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of PYY in a pharmaceutically acceptable carrier.  
   
   
       92 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of parathyroid hormone in a pharmaceutically acceptable carrier.  
   
   
       93 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of a peptide having a molecular weight of about 1-75 kD in a pharmaceutically acceptable carrier, with the proviso that the peptide is not insulin, calcitonin, and glucagon.  
   
   
       94 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount erythropoietin in a pharmaceutically acceptable carrier.  
   
   
       95 . A method as in claims  47 - 94  for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent such that the therapeutic agent persists in the cerebro-ventricular space for a time sufficient to ameliorate the disorder.  
   
   
       96 . A method for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent as in claims  87 - 95  such that the therapeutic agent persists in the cerebro-ventricular space for a time sufficient to ameliorate the disorder.  
   
   
       97 . A method of increasing absorption of a compound into the CSF of a subject comprising administering intranasally the compound and an absorption increasing amount of a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl joined by a linkage to a hydrophilic saccharide.  
   
   
       98 . The method of  claim 97 , wherein the alkyl glycoside has a concentration in the range of about 0.01% to 1.0%.  
   
   
       99 . The method of  claim 97 , wherein the alkyl has from 9 to 24 carbons.  
   
   
       100 . The method of  claim 97 , wherein the alkyl has from 9 to 14 carbon atoms.  
   
   
       101 . The method of  claim 97 , wherein the alkyl glycoside further has a hydrophile-lipophile balance number in the range of about 10 to 20.  
   
   
       102 . The method of  claim 97 , wherein the compound is a protein or a peptide.  
   
   
       103 . The method of  claim 102 , wherein the protein or peptide drug is selected from the group consisting of insulin and glucagon.  
   
   
       104 . The method of  claim 97 , and further comprising administering a protease or peptidase inhibitor.  
   
   
       105 . The method of  claim 97 , wherein the compound is administered in a format selected from the group consisting of a drop, a spray; an aerosol and a sustained-release format.  
   
   
       106 . A method of controlling caloric intake by administering a composition comprising a therapeutic effective amount of exendin-4, or related GLP-1 peptide, with an effective amount of TDM alkyl saccharide.  
   
   
       107 . A method of controlling blood glucose levels in a subject by administering to a subject a composition comprising a therapeutic effective amount of exendin-4, or related GLP-1 peptide, with an effective amount of Intravail alkyl saccharide.  
   
   
       108 . A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a mucosal delivery-enhancing agent wherein the mucosal delivery-enhancing agent is selected from: 
 (a) an aggregation inhibitory agent;    (b) a charge-modifying agent;    (c) a pH control agent;    (d) a degradative enzyme inhibitory agent;    (e) a mucolytic or mucus clearing agent;    (f) a ciliostatic agent;    (g) a membrane penetration-enhancing agent selected from: 
 (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long-chain amphipathic molecule; (vii) a small hydrophobic penetration enhancer; (viii) sodium or a salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or beta-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or salt thereof; (xiv) an N-acetylamino acid or salt thereof; (xv) an enzyme degradative to a selected membrane component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of the membrane penetration enhancing agents recited in (i)-(x);  
   (h) a modulatory agent of epithelial junction physiology;    (i) a vasodilator agent;    (j) a selective transport-enhancing agent; and    (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support or complex-forming species with which the compound is effectively combined, resulting in stabilization of the compound for enhanced nasal mucosal delivery, wherein the formulation of the compound with the intranasal delivery-enhancing agents provides for increased bioavailability of the compound in a blood plasma of a subject.    
   
   
       109 . The pharmaceutical composition of  claim 108 , further comprising a plurality of intranasal delivery-enhancing agents.  
   
   
       110 . The pharmaceutical composition of  claim 108 , wherein said mucosal delivery-enhancing agent(s) is/are selected from the group consisting of citric acid, sodium citrate, propylene glycol, glycerin, L-ascorbic acid, sodium metabisulfite, EDTA disodium, benzalkonium chloride, sodium hydroxide and mixtures thereof.  
   
   
       111 . The pharmaceutical composition of  claim 108 , wherein the alkyl has from 10 to 16 carbon atoms.  
   
   
       112 . A method of increasing absorption of a low molecular weight compound into the circulatory system of a subject comprising administering, via the ocular, nasal, nasolacrimal, inhalation, or CSF delivery route (a) the compound; (b) an absorption increasing amount of a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl joined by a linkage to a hydrophilic saccharide; and (c) a mucosal delivery-enhancing agent.  
   
   
       113 . The method of  claim 112 , wherein the alkyl glycoside has a concentration in the range of about 0.01% to 1.0%.  
   
   
       114 . The method of  claim 112 , wherein the alkyl has from 9 to 24 carbons.  
   
   
       115 . The method of  claim 112 , wherein the alkyl has from 9 to 14 carbon atoms.  
   
   
       116 . The method of  claim 112 , wherein the alkyl has from 10 to 16 carbon atoms.  
   
   
       117 . The method of  claim 112 , wherein the saccharide is selected from the group consisting of maltose, sucrose and glucose.  
   
   
       118 . The method of  claim 112 , wherein the alkyl glycoside further has a hydrophile-lipophile balance number in the range of about 10 to 20.  
   
   
       119 . The method of  claim 112 , wherein the linkage is selected from the group consisting of a glycosidic linkage, a thioglycosidic linkage, an amide linkage, a ureide linkage and an ester linkage.  
   
   
       120 . The method of  claim 112 , wherein the compound is a protein or a peptide.  
   
   
       121 . The method of  claim 112 , wherein the method comprises a protease or peptidase inhibitor.  
   
   
       122 . The method of  claim 112 , wherein the compound is administered in a format selected from the group consisting of a drop, a spray, an aerosol and a sustained-release format.  
   
   
       123 . The method of  claim 112 , wherein the compound is selected from nicotine, interferon, PYY, GLP-1, synthetic exendin-4, parathyroid hormone, human growth hormone, or a small organic molecule.  
   
   
       124 . A dosage dependent release composition comprising: 
 (a) a core comprising: 
 (i) at least one therapeutic agent or drug;  
 (ii) a surfactant comprising at least one alkyl glycoside and/or saccharide alkyl ester; and  
   (b) at least one membrane coating surrounding the core, wherein the coating is impermeable, permeable, semi-permeable or porous and becomes more permeable upon sustained contact with contents of the gastrointestinal tract.    
   
   
       125 . The membrane coating of  claim 124  further comprising an alkalizing agent and/or a plasticizer.  
   
   
       126 . The composition of  claim 124  wherein the core is in the form of a tablet, hard capsule or gel capsule.  
   
   
       127 . The composition of  claim 124 , wherein release of the drug is in a pH between about 4 and 7.  
   
   
       128 . The composition of  claim 124 , wherein release of the drug is in a pH between about 4 and 6.  
   
   
       129 . The composition of  claim 124 , wherein release of the drug is in a pH between about 4 and 5.  
   
   
       130 . The composition of  claim 124 , wherein the coating is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, cellulose acetate trimellitate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate malate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalate, shellac, styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl acrylate-methacrylic acid copolymer, butyl acrylate-styrene-acrylic acid copolymer, methacrylic acid-methyl methacrylate copolymei, methacrylic acid-ethyl acrylate copolymer, methyl acrylate-methacrylic acid-octyl acrylate copolymer, vinyl acetate-maleic acid anhydride copolymer, styrene-maleic acid anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-maleic acid anhydride copolymer, ethylene-maleic acid anhydride copolymer, vinyl butyl ether-maleic acid anhydride copolymer, acrylonitrile-methyl acrylate-maleic acid anhydride copolymer, butyl acrylate-styrene-maleic acid anhydride copolymer, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butylate phthalate and polyvinyl acetoacetal phthalate, or combinations thereof.  
   
   
       131 . The composition of  claim 124 , wherein the drug is selected from a group consisting of insulin like growth factor-I (IGF-I), somatomedin-C (SM-C), insulin, calcitonin, leptin, leptin derived short peptide (OB-3), hGH, human parathyroid hormone (PTH), melatonin, GLP-1 or Glucagon-like peptide-1, GiP, pituitary adenylate cyclase-activating polypeptide (PACAP), GM-1 ganglioside, nerve growth factor (NGF), nafarelin, Synarel®, (D-tryp6)-LHRH, FGF, VEGF antagonists, VEGF agonist, leuprolide, interferon-alpha, low molecular weight heparin, PYY, LHRH antagonists, LH, ghrelin antagonists, KGF, GDNF, G-CSF, Imitrex, Integrelin, Natrecor®, human B-type natriuretic peptide (hBNP), SYNAREL®, Sandostatin, Forteo, DDAVP® Nasal Spray, Cetrotide®, Antagon™, Angiomax, Accolate®, Exendin-4, SYMLIN®, desmopressin, glucagon, ACTH, C-peptide of insulin, GHRH and analogs (GnRHa), growth hormone releasing hormone, oxytocin, corticotropin releasing hormone (CRH), atrial natriuretic peptide (ANP), thyroxine releasing hormone (TRHrh), follicle stimulating hormone (FSH), prolactin, or tobramycin ocular.  
   
   
       132 . The composition of  claim 124 , wherein the coating is a porous coating.  
   
   
       133 . The composition of  claim 124 , further comprising a protease inhibitor.  
   
   
       134 . The composition of  claim 124 , wherein the alkyl alkyl has from about 10 to 24 carbon atoms.  
   
   
       135 . The composition of  claim 124 , wherein the alkyl alkyl has from about 10 to 20 carbon atoms.  
   
   
       136 . The composition of  claim 124 , wherein the alkyl alkyl has from about 10 to 16 carbon atoms.  
   
   
       137 . The composition of  claim 124 , wherein the alkyl group has from about 10 to 14 carbon atoms.  
   
   
       138 . The composition of  claim 124 , wherein the alkyl glycoside is tetradecyl maltoside (TDM).