WO2012176212A4

WO2012176212A4 - Carrier based nanogel formulation for skin targeting.

Info

Publication number: WO2012176212A4
Application number: PCT/IN2012/000130
Authority: WO
Inventors: Narayana KALA; Aurora Sundeep
Original assignee: V.B. Medicare Pvt. Ltd.
Priority date: 2011-06-20
Filing date: 2012-02-24
Publication date: 2013-02-28
Also published as: WO2012176212A1

Abstract

The invention comprises a lipid nano carrier based nanogel formulation of an active ingredient and method of their preparation. The formulation is specifically useful for dermal delivery or topical application of drugs, which may be a hydrophilic drug including 5-fluorouracil (5-FU) and acyclovir, or a hydrophobic drug such as isotretinoin. The invention is illustrated by a lipid nano carrier based nanogel formulation of 5-FU. A lipid nano carrier based nanogel formulation comprising 5- FU in a concentration of 0.001% to 10% w/w. A method of preparing lipid nano carrier based nanogel formulation of an active ingredient comprises the steps of: preparation of drug loaded vesicular lipid carrier dispersion, wherein the surface of vesicles of the lipid carrier contains a surfactant, probe sonicating the drug loaded vesicular lipid carrier dispersion of step (a.) to prepare a lipid nano carrier dispersion in nanometric size range, concentrating the lipid nano carrier dispersion in nanometric range by steps of subjecting the lipid nano carrier dispersion in nanometric size range of step (b.) either to (i) rotary evaporation, or (ii) freeze drying with or without a cryoproetctant, preparation of hydrophilic gel; and mixing of lipid nano carrier dispersion of step (c.) with hydrophilic gel of step (b) to form a lipid nano carrier based nanogel formulation.

Claims

AMENDED CLAIMS

received by the International Bureau on 27 December 2012 (27.12.2012)

1. A lipid nano carrier based nanogel formulation of an active ingredient.

2. A lipid nano carrier based nanogel formulation of claim 1 for dermal delivery or topical application.

3. A lipid nano carrier based nanogel formulation of claim 2, wherein the said active ingredient comprises a hydrophilic drug.

4. A lipid nano carrier based nanogel formulation of claim 2, wherein the said active ingredient comprises a lipophilic drug.

5. A lipid nano carrier based nanogel formulation of claim 3, wherein the said active ingredient comprises a hydrophilic drug selected from a group 5-fluorouracil (5-FU), acyclovir, colchicine, diclofenac and glucosamine.

6. A lipid nano carrier based nanogel formulation of claim 3, wherein the said active ingredient comprises a lipophilic drug selected from a group isotretinoin, amphotericin B, dithranol, calcipotriol, coaltar and tacrolimus.

7. A lipid nano carrier based nanogel formulation of claim 5 comprising 5-FU.

8. A lipid nano carrier based nanogel formulation of claim 5 comprising 5-FU in a concentration of 0.001 % to 10% w/w.

9 A lipid nano carrier based nanogel formulation of claim 2 comprising at least one active agent, a lipid, surfactant, hydrophilic

47 polymer, alkalizing agent, cryoprotectant, buffer, preservative, antioxidant, hydrating fluid and pharmaceutically acceptable additives.

10. A lipid nano carrier based nanogel formulation of claim 9, wherein the lipid io a phocph lipi/ Rolfi tpd from the QTOUP SOya phosphatidylcholine, egg phosphatidylcholine, disteryl phosphatidyl choline, phosphatidylethanolamine, phospatidylserine.

1. A lipid nano carrier based nanogel formulation of claim 10 wherein the said phospholipid is in concentration range of 1-20% w/w.

12. A lipid nano carrier based nanogel formulation of claim 9, wherein the surfactant is selected from group of non-irritating surfactant.

13. A lipid nano carrier based nanogel formulation of claim 12 wherein the said non-irritating surfactant is selected from the group comprising Vitamin E TPGS, sodium deoxycholate, sodium taurocholate, polyoxyethylene lauryl ether, polyoxyethylene-2-oleyl ether, and polyoxyethylene-2-stearyl ether.

14. A lipid nano carrier based nanogel formulation of claim 13 wherein the said surfactant is used in concentration range of 0.25-5.0% w/w

15. A lipid nano carrier based nanogel formulation of claim 9, wherein the hydrating fluid is selected from phosphate buffer saline (pH 6.8), phosphate buffer saline (pH 7.4) and 20% Tris buffer:25% Ammonia solution (1 :1).

16. A lipid nano carrier based nanoflel formulation of claim 9, wherein the hydrophillic polymers used as gel formers is selected from a cross-linked polymer,

17. A lipid nano carrier based nanogel formulation of claim 16 wherein the said cross-linked polymer is selected from the group comprising polyacrylate polymer, methyl cellulose, Poloxamer, hydroxy ethylcellulose and hydroxy propylcellulose.

18. A lipid nano carrier based nanogel formulation of claim 8 comprising 5-FU in a concentration of 5% w/w.

19. A lipid nano carrier based nanogel formulation of claim 8 having 60-80% of 5-FU in encapsulated form.

20. A lipid nano carrier based nanogel formulation of claim 8 wherein the said formulation has a good local bioavailability and sustaining the release of drug without showing the signs of skin irritation after the repeated administration.

21. A method of preparing lipid nano carrier based nanogel formulation of an active ingredient comprising the steps of:

a. preparation of drug loaded vesicular lipid carrier dispersion using a drug solution in a hydrating medium, wherein the vesicle membrane of the vesicular lipid carrier contains a surfactant;

b. probe sonicating the drug loaded vesicular lipid carrier dispersion of step (a.) to prepare a lipid nano carrier dispersion in nanomeric size range , c, concentrating the lipid nano carrier dispersion in nanomeric range of step (b) by subjecting the same dispersion either to (i) rotary evaporation, or (ii) freeze drying with or without a cryoproetctant.

d, preparation of hydrophilic gel; and

e, mixing of lipid nano carrier dispersion of step (c.) with hydrophilic gel of step (b) to form a lipid nano carrier based nanogel formulation.

, A method of claim 21 wherein:

a. preparation of drug loaded vesicular lipid carrier dispersion comprises steps of:

i. dissolving phospholipids, surfactant and others lipophilic additives in a small quantity of an organic solvent sufficient to dissolve the lipid, surfactant and additives,

ii. removing the organic solvent by a means of evaporation or under reduced pressure, removing final traces under vacuum to get a lipid film deposited,

iii. hydrating the deposited lipid film in a hydration medium by rotation to form lipid carrier suspended in the said hydration medium, wherein the said hydration medium shall contain hydrophilic drug that is intended for loading.

23. A method of claim 22 wherein the drug Is 5-FU and loading achieved is 1% w/w comprising steps of:

a. hydration medium being water or Phosphate buffer saline (PBS 6.8) or Phosphate buffer saline (PBS 7.4). b. dissolving 5-FU at a concentration of 10 mg/mL in the hydration medium,

c. hydrating the deposited lipid film claim 10 step (ii) with drug solution of step (b.) to form lipid carrier dispersed in the said hydration medium,

d. probe sonicating the drug loaded vesicular lipid carrier dispersion of step (a.) to prepare a lipid nano carrier dispersion in 100-200 nm or other nanometric size range , e. concentrating the lipid nano carrier dispersion in nanometric range by subjecting the same dispersion either to (i) rotary evaporation, or (ii) freeze drying with or without a cryoproetctant.

f. preparation of hydrophilic gel; and

g. mixing of lipid nano carrier dispersion of step (e.) with hydrophilic gel of step (b) to form a lipid nano carrier based nanogel formulation.

24. A method of claim 22 wherein the drug is 5-FU and loading achieved is 5% w/w comprising steps of:

a. hydration medium being an alkalizing medium.

51 b. dissolving 5-FU at a concentration of 100 mg/mL In the hydration medium,

c. hydratiny the deposited lipid film of claim 10 step (ii) ith drug solution of step (b.) to form lipid carrier dispersed in the said hydration medium,

d. probe sonicating the drug loaded vesicular lipid carrier dispersion of step (a.) to prepare a lipid nano carrier dispersion in nanometric size range , e. preparing a lipid nano carrier dispersion In nanometric range by steps of subjecting the lipid nano carrier dispersion in nanometric size range of step (b.) to rotary evaporation. f. preparation of hydrophilic gel; and

25. A method of preparation of hydrophilic gel of claim 21 comprising steps of:

a. adding and mixing appropriate quantity of a polymer to deionized water,

b. allowing the dispersion to hydrate and swell for 60 min., c. neutralize the dispersion with an alkali accompanied by gentle stirring,

d. agitating this mixture for 2 h with high speed stirrer until homogeneous clear hydrophilic gel is formed,

52 e. adding a preservative,

f. allowing to equilibrate the hydrophilic gel for at least 24 hours at room temperature prior to further use to make a lipid nano carrier based nanogel.

26. A method of preparation of lipid nano carrier based nanogel of claim 21 comprising step of mixing the lipid nano carrier dispersion with optimized hydrophilic gel under mechanical stirring for 1 h to result in to lipid nano carrier based Nanogel formulation.

27. A method of claim 24 wherein:

a. the said solvent is selected from a group comprising chloroform, methanol and diethyl ether, and

b. the amount of organic solvent in the mixture ranges from 1 - 2% w/w of the lipid, and

c. said rotation for hydration are at 60 rev/min for 1-2 hr.

28. A method of claim 25 wherein:

a. said polymer is a cross-linked polyacrylate polymer b. the said alkali is 98% triethanolamine,

c. said neutralization is done to reach a pH of 5.5 - 7.1 , d. said preservative is selected from the group methyl paraben, propyl paraben or benzyl alcohol.

29. A method of treating a dermal disease capable of treatment by topical administration of a therapeutically effective amount the formulation of claim 7 containing therapeutically effective concentration of 5-FU.

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30. A method of treating a dermal disease selected from acne, herpes lesions, inflammation, psoriasis cold sore, fungal and bacterial infection, wart, seborrheic eczema and cutaneous leishmaniasis by topical administration of a therapeutically effective amount the formulation of claim 7 containing therapeutically effective concentration of 5-FU.

31 . A method of claim 21 wherein the nano-carrier dispersion is loaded with 5-FU.

32. A method of claim 31 wherein the said loading achieved is 0.5 to 5.0 % w/w similar to clinical recommended concentration 0.5%, 1.0%, 2.0% and 5.0% w/w for its topical administration

33. A method of claim 21 wherein the nano-carrier dispersion is loaded with acyclovir.

34. A method of claim 33 wherein the said loading achieved is 5.0 % w/w similar to clinical recommended concentration 5.0% w/w for its topical administration

35. A method of claim 24 wherein the said alkalizing medium is 20% Tris buffer:25% Ammonia solution (1 :1).

36. A method of claim 30 of achieving enhanced Permeability and penetration of 5-FU reaching the dermis resulting in reduced risk of occurrence of Bowen's disease.

37. A lipid nano carrier based nanogel formulation of claim 7 comprising enhanced Permeability and penetration of 5-FU reaching the dermis resulting in reduced risk of occurrence of Bowen's disease.

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STATEMENT UNDER ARTICLE 19 (1 )

The applicant respectfully submits his response to Box no. V in the Written Opinion of the International Searching Authority.

Claim 8 has been amended to add a full stop. This is correction of a punctuation error.

Claim 20 has been amended to make it double spaced. This also is correction of a punctuation error.

Claim 21 has been amended to add a space between two words. This also is correction of a punctuation error.

Claim 22 has been amended to delete the phrase "including lipophilic drug to be used", which, as pointed out by the Authority, is an obvious mistake and contradiction. The deletion is also supported by the specification in general throughout and in particular by the "as filed" specification in description on page 14 lines 6 to 10. Claim 22 is further emended to insert words "that" and "ing" w hinh are meant only tn clarify the meaning and imprrwing the r.nnstn ir.tinn nf the sentence without adding any new meaning or without adding any new matter, Claim 24 is amended to delete the word "either" which has remained as an editing error since not alternative is mentioned in that claim.

Claim 33 is amended to insert a space; which is a correction of an obvious punctuation error.

Thus, no new matter has been added.

There may be a need to amend the description.

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