Liquid formulations for proteinic pharmaceuticals

• US 5,653,987 A
• Filed: 05/16/1995
• Issued: 08/05/1997
• Est. Priority Date: 05/16/1995
• Status: Expired due to Term

• Current Assignee: Pankaj Modi, Subash Chandarana
• Original Assignee: Pankaj Modi, Subash Chandarana
• Inventors: Modi, Pankaj, Chandarana, Subash
• Primary Examiner(s): Hulina, Amy
• Application Number:
  US08/442,358
• Time in Patent Office: 812 Days
• Field of Search: 424/400, 424/434, 424/455, 514/946, 514/947
• US Class Current: 424/400
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A liquid pharmaceutical agent formulation suitable for oral or nasal delivery comprises a proteinic pharmaceutical agent, water and at least two absorption enhancing compounds. The absorption enhancing compounds are selected from sodium salicylate, sodium lauryl sulphate, disodium ethylenediaminetetraacetic acid (disodium EDTA), oleic acid, linoleic acid, monoolein, lecithin, lysolecithin, deoxycholate, sodium deoxycholate, chenodeoxycholate, taurodeoxycholate, glycochenodeoxycholate, polyoxyethylene X-lauryl ether wherein X is from 9 to 20, sodium tauro-24, 25-dihydrofusidate, polyoxyethylene ether, polyoxyethylene sorbitan esters, p-t-octylphenoxypolyoxyethylene, N-lauryl-β-D-maltopyranoside, 1-dodecylazacycloheptane-2-azone and phospholipids, wherein the amount of each of the absorption enhancing compounds is present in a concentration of from 1 to 10 wt./wt. % of the total formulation. Preferably each of the absorption enhancing compounds is present in a concentration of from 1.5 to 3.5 wt./wt. % The formulation is particulary adapted to oral delivery of insulin.

Claims

1. A liquid pharmaceutical agent formulation suitable for oral or nasal delivery comprising a proteinic pharmaceutical agent, water and at least two absorption enhancing compounds, wherein said absorption enhancing compounds are selected from the group consisting of a combination of deoxycholate, chenodeoxycholate, and polyoxyethylene 9-lauryl ether, a combination of sodium salicylate, deoxycholate, chenodeoxycholate, and polyoxyethylene 9-lauryl ether, a combination of sodium deoxycholate, chenodeoxycholate, polyoxyethylene 9-lauryl ether and monoolein, a combination of deoxycholate, chenodeoxycholate and sodium salicylate, a combination of deoxycholate, sodium salicylate and sodium lauryl sulphate, a combination of oleic acid, linoleic acid and sodium lauryl sulphate, a combination of monoolein, deoxycholate and polyoxyethylene 9-lauryl ether, a combination of deoxycholate, chenodeoxycholate, polyoxyethylene 9-lauryl ether and sodium tauro-24, 25-dihydrofusidate, a combination of sodium deoxycholate, chenodeoxycholate, polyoxyethylene 9-lauryl ether and sodium tauro-24, 25-dihydrofusidate, a combination of deoxycholate, chenodeoxycholate, taurodeoxycholate, polyoxyethylene 9-lauryl ether and monoolein, a combination of chenodeoxycholate, glycochenodeoxycholate, polyoxyethylene 9-lauryl ether and sodium tauro-24, 25-dihydrofusidate, a combination of chenodeoxycholate, sodium lauryl sulphate and disodium EDTA, a combination of deoxycholate, chenodeoxycholate, polyoxyethylene 9-lauryl ether and disodium EDTA, a combination of sodium salicylate, disodium EDTA and polyoxyethylene 9-lauryl ether, a combination of monoolein, oleic acid and polyoxyethylene sorbitan ester, a combination of monoolein, oleic acid, polyoxyethylene sorbitan ester and sodium lauryl sulphate, and a combination of linoleic acid, monoolein and sodium salicylate, wherein the amount of each of the absorption enhancing compounds is present in a concentration of from 1 to 10 wt./wt. % of the total formulation.

2. A liquid pharmaceutical agent formulation according to claim 1 wherein the absorption enhancing compound compositions are selected from the group consisting of i) a combination of deoxycholate, chenodeoxycholate and sodium salicylate, ii) a combination of sodium salicylate, deoxycholate and sodium lauryl sulphate, iii) a combination of chenodeoxycholate, sodium lauryl sulphate and disodium EDTA and iv) a combination of monoolein, oleic acid and polyoxyethylene sorbitan ester, and v) a combination of deoxycholate, chenodeoxycholate and polyoxyethylene 9-lauryl ether.

3. A liquid pharmaceutical agent formulation according to claim 1 wherein the formulation contains at least one protective polymer for slow release of the pharmaceutical agent.

4. A liquid pharmaceutical agent formulation according to claim 1 wherein the formulation contains at least one protective polymer selected from the group consisting of polyvinyl alcohol, polyethylene glycol and gelatin.

5. A liquid pharmaceutical agent formulation according to claim 1 wherein the formulation contains an antioxidant.

6. A liquid pharmaceutical agent formulation according to claim 1 wherein the formulation contains an antioxidant selected from the group consisting of tocopherol, deteroxime mesylate, methyl paraben and ascorbic acid.

7. A liquid pharmaceutical agent formulation according to claim 1 wherein the formulation contains at least one protease inhibitor.

8. A liquid pharmaceutical agent formulation according to claim 1 wherein the formulation contains a protease inhibitor selected from the group consisting of bacitracin, soyabean trypsin and aprotinin in a concentration of from 1 to 3 wt./wt. %.

9. A liquid pharmaceutical agent formulation according to claim 1 wherein the pharmaceutical agent is selected from the group consisting of insulin, heparin, hirugen, hirulos, huridine, mumps, measles and rubella vaccine, typhoid vaccine, hepatitis A vaccine, hepatitis B vaccine, herpes simplex virus, bacterial toxoids, cholera toxin B-subunit, influenza vaccine virus, bordetala pertussis, vaccinia virus, adenovirus, canary pox, polio vaccine virus, plasmodium falciparum, bacillus calmette geurin (BCG), klebsiella pneumoniae, HIV envelop glycoproteins, bovine somatropine, estrogens, androgens, insulin growth factors, interleukin-I, interleukin-II and cytokins.

10. A liquid insulin formulation according to claim 1 wherein the pharmaceutical agent is insulin.

11. A liquid insulin formulation according to claim 10 wherein the formulation also contains at least one inorganic salt which opens channels in the gastrointestinal tract, at least one protective polymer and at least one protease inhibitor.

12. A liquid insulin formulation according to claim 11 wherein the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate, the protective polymer is selected from the group consisting of polyvinyl alcohol, polyethylene glycol and gelatin, and the protease inhibitor is selected from the group consisting of bacitracin, soyabean trypsin and aprotinin.

13. A liquid insulin formulation according to claim 12 which also contains an antioxidant.