Oral administration of unstable or poorly-absorbed drugs

Abstract

The disclosure relates to a dosage forms and combinations of dosage forms useful for effective oral administration of drugs which are otherwise unsuitable for oral administration, owing to acid- and/or protease-mediated degradation. The dosage forms include a self-microemulsifying drug delivery system (SMEDDS) with which the drug is combined and an antacid. When co-administered to a mammal, the dosage form(s) can prevent drug degradation by the strong acid and digestive enzymes normally present in the gastric environment, and can improve water-soluble drug absorption in gastrointestinal (GI) tract. The dosage forms can be used to effectively administer insulin by an oral route, for example, such as in the form of a powder that can be stored for long periods and reconstituted with water or another fluid shortly before administration.

What is claimed is: 
     
         1 . A dosage form for orally administering a gastrically impractical drug to the bloodstream of a mammal, the dosage form comprising
 an antacid sufficient to raise the gastric pH of the mammal to at least about 3 upon ingestion of the dosage form and   a combination of a therapeutically effective amount of the drug and a surfactant system that includes a non-ionic surfactant, as a self-microemulsifying drug delivery system (SMEDDS), the identity and amount of the surfactant system being sufficient to induce spontaneous emulsification upon contact between the combination and an aqueous medium under conditions of mild mechanical agitation, wherein the drug is a polypeptide.   
     
     
         2 . The dosage form of  claim 1 , wherein the identity and amount of the surfactant system is sufficient to induce spontaneous emulsification upon contact between the combination and a two-fold or four-fold or nine-fold excess of distilled water under conditions of mechanical agitation characteristic of the stomach of the mammal. 
     
     
         3 . The dosage form of  claim 1 , wherein the combination includes the antacid. 
     
     
         4 . The dosage form of  claim 1 , wherein the antacid is sufficient to raise the gastric pH of the mammal to at least about 3.4 upon ingestion of the dosage form. 
     
     
         5 . The dosage form of  claim 1 , wherein the combination is in the form of a first composition and the antacid is in the form of a second composition. 
     
     
         6 . The dosage form of  claim 5 , wherein the first and second compositions are present at distinct portions of the dosage form. 
     
     
         7 . The dosage form of  claim 5 , wherein the first composition and the second composition are in liquid or solid forms. 
     
     
         8 . The dosage form of  claim 1 , wherein the identity and amount of the surfactant system are selected such that the average droplet size of the emulsion formed upon contact between the combination and the aqueous medium is not greater than about 2000 nanometers. 
     
     
         9 . The dosage form of  claim 8 , wherein the average droplet size is not greater than about 800 nanometers. 
     
     
         10 . The dosage form of  claim 1 ,
 wherein the drug is selected from the group consisting of insulin peptides, growth hormones, erythropoietin, monoclonal antibodies, and antibody fragments; or   wherein the drug is insulin peptides; or   wherein the drug is naturally-occurring forms of insulin, synthetic insulins or insulin-like peptides.   
     
     
         11 . The dosage form of  claim 10 , wherein the drug is selected from the group consisting of anthrotherapeutic insulins. 
     
     
         12 . The dosage form of  claim 11 , wherein the drug is a human insulin peptide. 
     
     
         13 . The dosage form of  claim 1 , wherein the drug is a hydrophilic polypeptide drug. 
     
     
         14 . The dosage form of  claim 1 , wherein the surfactant system includes at least one surfactant selected from the group consisting of polyglycolized glycerides having at least one acyl moiety and propylene glycol esters of fatty acids. 
     
     
         15 . The dosage form of  claim 1 , wherein the combination further comprises a polyol solvent. 
     
     
         16 . The dosage form of  claim 15 , wherein the polyol solvent is selected from the group consisting of glycerol, propylene glycol, and polyethylene glycols that are liquid at 20 degrees Celsius. 
     
     
         17 . The dosage form of  claim 1 , wherein the antacid is sufficient to raise the gastric pH of the animal to at least about 3 within about one minute following ingestion of the dosage form. 
     
     
         18 . The dosage form of  claim 1 , wherein the antacid is selected from the group consisting of sodium bicarbonate, magnesium hydroxide, calcium carbonate, aluminum hydroxide, and combinations of these. 
     
     
         19 . The dosage form of  claim 1 , wherein the antacid is sufficient to neutralize at least about 1 milliequivalent of stomach acids. 
     
     
         20 . A kit comprising the dosage form of  claim 1  and an aliquot of the aqueous medium in an amount sufficient to dissolve or suspend the antacid and to emulsify the combination. 
     
     
         21 . A kit comprising
 a first dosage form comprising an antacid sufficient to raise the gastric pH of the mammal to at least about 3 upon ingestion of the first dosage form and   a second dosage form comprising a combination of a therapeutically effective amount of a gastrically impractical drug and a surfactant system that includes a non-ionic surfactant, as a self-microemulsifying drug delivery system (SMEDDS), the identity and amount of the surfactant system being sufficient to induce spontaneous emulsification upon contact between the second dosage form and an aqueous medium under conditions of mild mechanical agitation,   wherein the drug is a polypeptide.   
     
     
         22 . The dosage form of  claim 1 ,
 wherein the drug is insulin peptides;   wherein the surfactant system includes
 at least one polyglycolized glyceride having at least one acyl moiety and propylene glycol esters of fatty acids, preferably selected from the group consisting of polyglycolized glycerides include oleoyl polyoxylglycerides polyoxyl-6 glycerides such as Labrafil® M-1944CS), linoleoyl polyoxylglycerides (linoleoyl polyoxyl-6 glycerides such as Labrafil® M-2125CS), caprylocaproyl polyoxylglycerides (PEG-6 caprylic/capric glycerides such as SOFTIGEN® 767), caprylocaproyl polyoxyl-8 glycerides (e.g., Labrasol®), and lauroyl polyoxylglycerides (Gelucire® 44/14), and 
 optionally one or more additional surfactants, preferably selected from the group consisting of polysorbate, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, glyceryl monooleate, glyceryl monolinoleate, medium-chain triglycerides, polyglyceryl oleate, lauroyl polyoxylglyceride, stearoyl polyoxylglycerides, and combinations of these; 
   wherein the combination further comprises a polyol solvent, preferably selected from the group consisting of glycerol, propylene glycol, and polyethylene glycols that are liquid at 20 degrees Celsius; and   wherein the antacid is selected from the group consisting of sodium bicarbonate, magnesium hydroxide, calcium carbonate, aluminum hydroxide, and combinations of these.   
     
     
         23 . The dosage form of  claim 1 , wherein the dosage form is in a unitary dosage form or a multi-compartment dosage form. 
     
     
         24 . The dosage form of  claim 1 , wherein the dosage form includes tablets, capsules, powder, granules, solution and/or suspension. 
     
     
         25 . The dosage form of  claim 1 , wherein the dosage form is a substantially homogenous composition. 
     
     
         26 . A dosage form of orally administering a gastrically impractical drug, comprising:
 an antacid sufficient to raise the gastric pH of the mammal to at least about 3 upon ingestion of the dosage form,
 a surfactant system that includes a non-ionic surfactant, as a self-microemulsifying drug delivery system (SMEDDS), the identity and amount of the surfactant system being sufficient to induce spontaneous emulsification upon contacting an aqueous medium under conditions of mild mechanical agitation, and 
 a therapeutically effective amount of the drug, 
 wherein the drug is a polypeptide. 
   
     
     
         27 . The dosage form of  claim 26 , wherein the drug is selected from the group consisting of insulin peptides, growth hormones, erythropoietin monoclonal antibodies, and antibody fragments; or
 wherein the drug is insulin peptides; or   wherein the drug is naturally-occurring forms of insulin, synthetic insulins or insulin-like peptides.   
     
     
         28 . The dosage form of  claim 26 , wherein the dosage form is in a unitary dosage form or a multi-compartment dosage form. 
     
     
         29 . The dosage form of  claim 26 , wherein the dosage form includes tablets, capsules, powder, granules, solution and/or suspension 
     
     
         30 . The dosage form of  claim 26 , wherein the dosage form is a substantially homogenous composition. 
     
     
         31 . The dosage form of  claim 1 , wherein the dosage form is selected from the group consisting of:
 (i) a dosage form comprising an insulin peptide, Labrasol, propylene glycol, hydrochloride (HCl), Lauroglycol FCC and Tween 80, in combination with sodium bicarbonate (NaHCO 3 );   (ii) a dosage form comprising an insulin peptide, Softigen, propylene glycol, hydrochloride (HCl), Lauroglycol FCC and Tween 80, in combination with sodium bicarbonate (NaHCO 3 );   (iii) a dosage form comprising an insulin peptide, Labrafil, glycerol, a polyethylene glycol, hydrochloride (HCl), Cremophor RH40 and Tween 80, in combination with sodium bicarbonate (NaHCO 3 );   (iv) a dosage form comprising an insulin peptide, Labrasol, glycerol, and sodium bicarbonate, optionally in combination with water;   (v) a dosage form comprising an insulin peptide, Labrasol, glycerol, sodium bicarbonate and magnesium hydroxide, optionally in combination with water,   (vi) a dosage form comprising an insulin peptide, Labrasol, sodium bicarbonate and an adsorbant (such as Aerosil, Neusilin), optionally in combination with water; and   (vii) a dosage form comprising a first part comprising an insulin peptide, sodium bicarbonate, mannitol and povidone K-30, and a second part comprising Labrasol, glycerol and water.   
     
     
         32 . The dosage form of  claim 26 , wherein the dosage form is selected from the group consisting of:
 (i) a dosage form comprising an insulin peptide, Labrasol, propylene glycol, hydrochloride (HCl), Lauroglycol FCC and Tween 80, in combination with sodium bicarbonate (NaHCO 3 );   (ii) a dosage form comprising an insulin peptide, Softigen, propylene glycol, hydrochloride (HCl), Lauroglycol FCC and Tween 80, in combination with sodium bicarbonate (NaHCO 3 );   (iii) a dosage form comprising an insulin peptide, Labrafil, glycerol, a polyethylene glycol, hydrochloride (HCl), Cremophor RH40 and Tween 80, in combination with sodium bicarbonate (NaHCO 3 );   (iv) a dosage form comprising an insulin peptide, Labrasol, glycerol, and sodium bicarbonate, optionally in combination with water;   (v) a dosage form comprising an insulin peptide, Labrasol, glycerol, sodium bicarbonate and magnesium hydroxide, optionally in combination with water;   (vi) a dosage form comprising an insulin peptide, Labrasol, sodium bicarbonate and an adsorbant (such as Aerosil, Neusilin), optionally in combination with water; and   (vii) a dosage form comprising a first part comprising an insulin peptide, sodium bicarbonate, mannitol and povidone K-30, and a second part comprising Labrasol, glycerol and water.   
     
     
         33 . The dosage form of  claim 10 , wherein the insulin has an effect on the patient of rapid onset within 15-30 minutes after administration and short duration of action, falling to less than 25% of maximal activity in less than 5 hours. 
     
     
         34 . The dosage form of  claim 22 , wherein the insulin has an effect on the patient of rapid onset within 15-30 minutes after administration and short duration of action, falling to less than 25% of maximal activity in less than 5 hours. 
     
     
         35 . The dosage form of  claim 27 , wherein the insulin has an effect on the patient of rapid onset within 15-30 minutes after administration and short duration of action, falling to less than 25% of maximal activity in less than 5 hours.