CA2422580A1

CA2422580A1 - Selfemulsifiable formulation having enhanced bioabsorption and immunosuppression activities

Info

Publication number: CA2422580A1
Application number: CA002422580A
Authority: CA
Inventors: Saibal Chakravorty; Prasad Bharti
Original assignee: Rpg Life Sciences Limited; Saibal Chakravorty; Prasad Bharti
Current assignee: RPG Life Sciences Ltd
Priority date: 2000-09-18
Filing date: 2000-09-18
Publication date: 2002-03-21
Anticipated expiration: 2020-09-18
Also published as: SI1333851T1; AU2001225459C1; PT1333851E; CA2422580C; ES2292496T3; AU2545901A; DE60036137T2; DE60036137D1; MXPA02004900A; BR0013813A; EP1333851A1; EP1333851B1; US7056530B1; WO2002022158A1; AU2001225459B2; ATE370744T1

Abstract

A selfemulsifiable formulation comprising of lipophilic system consisting of medium chain triglyceride of caprylic acid and capric acid, and of labrasol, wherein labrasol also serves as surfactant, which is combined with other selected surfactants, like cremophore RH 40 and/or polysorbate 80 is disclosed, wherein said formulation also comprises of immunosuppression agen t essentially cyclosporine, hydrophilic agent preferably ethanol, antioxidant preferably alpha-tocopherol and preservative preferably benzyl alcohol, and said formulation is prepared by dissolving immunosuppression agent in hydrophilic agent followed by entrapping with lipophilic agent and subsequen t treatment with surfactants, preservative and antioxidant, and is filled in soft-gelatine shell capable of rupturing in less than 10 minutes to deliver said formulation in upper part of gastrointestinal tract, wherein it forms thermodynamically stable oil in water microemulsions in situ to have enhance d bioavailability and bioabsorption of immunosuppression agent, which can show its enhanced immunosuppression activities thereby.

Claims

1. A selfemulsifiable formulation for oral administration, wherein said formulation essentially comprises of immunosuppression agent, hydrophilic agent, lipophilic agent, one or more of surfactants, antioxidant and preservative, wherein said immunosuppression agent is preferably lactam macrolide having immunosuppression activity;
said hydrophilic agent is selected from a group consisting of pharmaceutically acceptable C1-5 alkyl, tetrahydrofuryl diether, tetrahydrofuryl partial ether, low molecular weight monooxy-alkane-diol, low molecular weight polyoxy-alkane-diol, 1,2-propyleneglycol ethanol;
said lipophilic agent is selected from a group consisting of medium chain monoglycerides, medium chain diglycerides, mixed esters of saturated fatty acids, like caprylic and/or capric acids, medium chain triglycerides of caprylic and/or capric acids, said one or more of surfacants are selected from a group consisting of hydrogenated vegetable oils polyoxyethylene sorbitan fatty acids, transesterified caprylic and/or capric glycerides;
said antioxidant is selected from a group consisting of alpha-tocopherol, ascorbyl palmitate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate; and said preservative is selected from a group consisting of ethanol, benzyl alcohol.

2. A selfemulsifiable formulation, as claimed in claim 1, wherein preferred said lipophilic agent is medium chain triglyceride of caprylic acid and capric acid.

3. A selfemulsifable formulation, as claimed in claim 1 and 2, wherein said medium chain triglyceride of caprylic acid and capric acid has specific gravity of about 0.93 to 0.96, refractive index of about 1.44 to 146, acid value less than about 0.2, saponification value of about 3t0 to 360 and iodine value less than about 1 and water content less than about 0.5.

4. A selfemulsifiable formulation, as claimed in claim 1, wherein said immunosuppression agent is particularly cyclosporine, more particularly cyclosporine-A having immunosuppression activity.

5. A selfemulsifiable formulation, as claimed in claim 1, wherein said hydrophilic agent is additionally selected from a group consisting of pharmaceutically acceptable lower (C1-4) alkanols, like ethanol; alkylene glycol monoalkyl ethers, like diethylene glycol monoethyl ethers, transcutol, glycofural (known as tertrahydrofuryl) alcohol polyethylene glycol ether. The preferred hydrophilic agent is lower alkanol, more preferable hydrophilic agent is ethanol.

6. A selfemulsifiable formulation, as claimed in claim 1, wherein said one or more of surfactants are additionally selected from a group consisting of saturated polyglycolysed C8 to C10 glycerides, like transesterified caprylic and/or capric glycerides, particularly PEG-8 caprylic and/or capric acid glyceride;
polyoxyethylene sorbitan fatty acid esters, like polysorbate 20, polysorbate 40, polysorbate 80, more preferably polysorbate 80; polyoxyethylene castor oil derivatives, like cremophor RH 40, cremophore EL, preferably cremophore RH 40.

7. A selfemulsifiable formulation, as claimed in claims 1 and 6, wherein said caprylic and cupric acid glyceride (labrasol) exhibits specific gravity of about 0.930 to 0.960, refractive index of about 1.44 to 1.452, acid value less than about 0.2, saponification value of about 85 to 105, peroxide value less than about 6Ø
free glycerol content less than about 5.0%, ethylene oxide content of about 1.0 ppm, water content less than about 1.0%, cupric acid less than about 2.0%, caprylic acid (C8) about 50 to 80%, capric acid (C10) about 20 to 50%, cupric acid (C12) less than about 3% and myristic acid (C14) less than about 1.0%, hydrophilic liophilic balance value of about 14.

8. A selfemulsifiable formulation, as claimed in claim 1, wherein said immunosuppression agent is taken in an amount of about 2 to 10%, preferably in an amount o f about 5 to 10%.

9. A selfemulsifiable formulation, as claimed in claim 1, wherein said immunosuppression agent and hydrophilic agent are taken in ratio of about 1:0.5, more preferably of about 1:2.5 by weight.

10. A selfemulsifiable formulation, as claimed in claim 1, wherein said lipophilic agent is taken in the ratio of about 1:0.5, preferably of about 1:2, more preferably of about 1:4 by weight.

11. A selfemulsifiable formulation, as claimed in claim 1, wherein said one or more of surfactants are taken in the ratio of about 2:1, preferably of about 3:1, more preferably of about 4:1 by weight with respect to lipophilic agent.

12. A selfemulsifiable formulation, as claimed in claim 1, wherein said surfactant is combination of labrasol and cremophore RH 40 or labrasol and polysorbate 80 and are taken in the ratio of about 1:1, preferably of about 2.5:1, more preferably of about 4.5:1 by weight.

13. A selfemulsifiable formulation, as claimed in claim 1, wherein said surfactant is combination of labrasol, cremophor RH 40, polysorbate 80 is taken in the ratio of about 4:1:1.5 by weight respectively.

14. A selfemulsifiable formulation, as claimed in claim 1, wherein said preservative is preferably benzyl alcohol and is taken in the amount of about 0.5 to 1 % by weight.

15. A selfemulsifiable formulation, as claimed in claim 1, wherein said antioxidant is preferably alpha-tocopherol and is taken in the amount of about 0.0008 to 0.0009%.

16. A selfemulsifiable formulation, as claimed in claim 1, wherein said formulation forms microemulsions of particle size less than 200 nm, preferably less than nm on contact with gastric juice or aqueous medium.

17. A selfemulsifiable formulation, as claimed and described herein above.

18. A method of preparation of selfemulsifiable formulation according to claims 1 to 17, wherein said method comprises of following steps;
a) dissolution of immunosuppression agent in hydrophilic agent, b) entrapping of solubilised immunosuppression agent with lipohilic agent, c) treatment of oii entrapped solubilised form of drug with. one or more of surfactants, d) treatment of solubilised drug entrapped with oil and one or more of surfactants with preservative and antioxidant.

19. A method of preparation of selfemulsifiable formulation as claimed in claim 18 and described herein above.

20. A selfemulsifiable formulation, as claimed in claims 1 to 14, wherein said formulation is made available in a soft shell, wherein the said shell essentially comprises of gelatin, glycerin, water and one or more of preservatives, like methyl paraben, propyl paraben, and one or more of colorants, like iron oxide black, titanium dioxide.

21. A shell according to claim 20, wherein gelatin is in taken in an amount of about 35 to 50% by weight.

22. A shell according to claim 20, wherein glycerin is taken in an amount of about 15 to 30% by weight.

23. A shell according to claim 20, wherein the preservatives are taken in an amount of about 0.2% by weight.

24. A shell according to claim 20, wherein water is taken in an amount of about 30 to 45% by weight.

25. A shell according to claim 20, wherein colorant is taken in an amount of about 0.5% by weight.

26. A shell for formulation as/claimed in 20 to 25 and described herein above.

27. A selfemulsifiable formulation, as claimed herein above, wherein said formulation is administered in soft shell or hard shell or in solution form.

28. A selfemulsifiable formulation, as claimed herein above, wherein said formulation is administered for immunosuppression therapy.