Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials

• US RE47,033 E1
• Filed: 04/17/2017
• Issued: 09/11/2018
• Est. Priority Date: 08/04/2003
• Status: Active Grant

• Current Assignee: Lonza Bend Incorporated (Lonza Group AG)
• Original Assignee: Bend Research Inc. (Lonza Group AG)
• Inventors: Babcock, Walter C., Friesen, Dwayne T., Shanker, Ravi M., Smithey, Daniel T.
• Primary Examiner(s): Kugel, Timothy J
• Application Number:
  US15/489,613
• Time in Patent Office: 512 Days
• Field of Search: 424486
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/1611 Inorganic compounds

Abstract

A pharmaceutical composition comprises a solid adsorbate comprising a drug adsorbed onto a substrate and a lipophilic microphase-forming material. The solid adsorbate may also be co-administered with a lipophilic microphase-forming material to an in vivo use environment. The compositions of the present invention enhance the concentration of drug in a use environment.

Claims

1. A composition comprising:

(a) a spray-dried solid dispersion adsorbate comprising a completely amorphous drug and a concentration enhancing polymer adsorbed onto an inorganic oxide substrate, and wherein said drug in said adsorbate is substantially completely amorphous and

(b) a lipophilic microphase-forming material selected from the group consisting of medium-chain glyceryl mono-, di-, and tri-alkylates, sorbitan esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), and mixtures thereof;

said composition having a mass ratio of said lipophilic microphase-forming material to said drug of from 0.1 to 500, and wherein said lipophilic microphase forming material is co-adsorbed with said drug onto said substrate of the spray-dried solid dispersion adsorbate;

wherein said lipophilic microphase-forming material is water immiscible and said drug has a partition coefficient K_p between a use environment and said lipophilic microphase-forming material of about 10 or more.

2. The composition of claim 1 wherein said lipophilic microphase-forming material is present in a sufficient amount so that said composition provides concentration enhancement of said drug in a use environment relative to at least one of a first control composition and a second control composition;

wherein (i) said first control composition consists essentially of an equivalent amount of said solid adsorbate with no lipophilic microphase-forming material present;

(ii) said second control composition consists essentially of an equivalent amount of said drug in unadsorbed form with an equivalent amount of said lipophilic, microphase-forming material.

3. The composition of claim 2 wherein said composition provides a relative bioavailability of at least 1.25-fold relative to at least one of said first control composition and said second control composition.

4. The composition of claim 1 wherein said lipophilic microphase-forming material forms lipophilic microphases in said use environment having a characteristic diameter of less than about 100 μ

m.

5. The composition of claim 1 wherein said mass ratio of said lipophilic microphase-forming material to said drug is from 0.1 to 100.

6. The composition of claim 1 wherein said solid adsorbate and said lipophilic microphase-forming material are both present in a single dosage form.

7. The composition of claim 1 wherein said composition is solid at 25°

C.

8. The composition of claim 1 wherein said composition provides synergistic enhancement.

9. The composition of claim 1 wherein said drug is selected from the group consisting of antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, anti-atherosclerotic agents, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer'"'"'s disease agents, antibiotics, antidepressants, and antiviral agents, glycogen phosphorylase inhibitors, and cholesteryl ester transfer protein inhibitors.

10. The composition of claim 1 wherein said concentration-enhancing polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose, poloxamers, polyvinylpyrrolidone, polyvinyl alcohols that have at least a portion of their repeat units in hydrolyzed form, and mixtures thereof.

11. The composition of claim 1 further comprising a second concentration-enhancing polymer wherein said second concentration enhancing polymer is not adsorbed to said substrate.

12. The composition of claim 11 wherein said second concentration-enhancing polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose, poloxamers, polyvinylpyrrolidone, polyvinyl alcohols that have at least a portion of their repeat units in hydrolyzed form, and mixtures thereof.

13. A solid dosage form comprising the composition of claim 1, wherein said lipophilic, microphase-forming material comprises from 10wt % to 80wt % 10 wt % to 80 wt % of said solid dosage form, and said dosage form is selected from the group consisting of a tablet and a capsule.

14. The composition of claim 1 wherein said substrate is selected from the group consisting of SiO₂, TiO₂, ZnO₂, ZnO, Al₂O₃, MgAlSilicate, CaSilicate, AIOH₂ AlOH₂, zeolites, and inorganic molecular sieves.

15. The composition of claim 1 wherein said lipophilic microphase-forming material is selected from sorbitan fatty acid esters, alpha tocopheryl polyethylene glycol 1000succinate 1000 succinate (TPGS), and mixtures thereof.

16. The composition of claim 1 wherein said solid adsorbate is formed by spraying a spray suspension comprising said drug, said lipophilic microphase-forming material, and said concentration-enhancing polymer, dissolved in a solvent having said substrate suspended therein, and the solvent is removed to form a solid powder in less than 100 seconds.