Formulation for topical non-invasive application in vivo

• US 7,175,850 B2
• Filed: 06/22/2001
• Issued: 02/13/2007
• Est. Priority Date: 12/23/1998
• Status: Expired due to Fees

• Current Assignee: IDEA AG
• Original Assignee: IDEA AG
• Inventors: Cevc, Gregor
• Primary Examiner(s): Hoffman; Susan Coe
• Application Number:
  US09/887,493
• Publication Number:
  US 20020064524A1
• Time in Patent Office: 2,062 Days
• Field of Search: 424401-450
• US Class Current: 424/401
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 7/06 : Antianaemics

Abstract

A formulation comprising molecular arrangements capable of penetrating pores in a barrier, owing to penetrant adaptability, despite the fact that the average diameter of said pores is smaller than the average penetrant diameter, provided that the penetrants can transport agents or else enable agent permeation through the pores after penetrants have entered pores, characterized in that the formulation comprises at least one consistency builder in an amount that increases the formulation to maximally 5 Nm/s so that spreading over, and retention at, the application area is enabled and/or at least one antioxidant in an amount that reduces the increase of oxidation index to less than 100% per 6 months and/or at least one microbicide in an amount that reduces the bacterial count of 1 million germs added per g of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, after a period of 4 days.

Claims

1. A formulation comprising penetrants being capable of penetrating the pores of a barrier, the average diameter of said pores being smaller than the average diameter of said penetrants, wherein said penetrants can transport agents or enable agent penetration through said pores after said penetrants have entered said pores, wherein the formulation further comprisesat least one antioxidant in an amount that reduces the increase of oxidation index to less than 100% per 6 months, wherein the antioxidant is selected from the group consisting of between 0.0025 and 0.2 w-% of butylated hydroxyanisol, between 0.0025 and 0.2 w-% of butylated hydroxytoluene, between 0.001 and 2 w-% of tertiary butylhydroquinone, between 0.001 and 2 w-% of propyl gallate, between 0.005 and 5 w-% of tocopherols, between 0.001 and 5 w-% of ascorbic acid esters, between 0.001 and 5 w-% of ascorbic acid, between 0.001 and 5 w-% of sodium bisulphite, between 0.001 and 5 w-% of sodium metabisulphite, between 0.0001 and 2 w-% of thiourea, between 0.01 and 5 w-% of cysteine, between 0.01 and 5 w-% of monothioglycerol, between 0.0005–

2 w-% of nordihydroguaiaretic acid, between 0.005 and 5 w-% of glutathione, between 0.001 and 5 w-% of EDTA, and between 0.001 and 5 w-% of citric acid, based on the total weight of the formulation; and

2) at least one microbiocide in an amount that reduces the bacterial count of 1 million germs added per gram of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, after a period of 4 days, wherein the microbicide is selected from the group consisting of up to 10 w-% of ethyl alcohol, up to 10 w-% of propyl alcohol, up to 10 w-% of butyl alcohol, up to 10 w-% of benzyl alcohol, between 0.3–

0.6 w-% of chlorobutanol, between 0.05–

0.2 w-% of parabens, between 0.05–

0.2 w-% of methyl paraben, between 0.002–

0.02 w-% of propyl paraben, between 0.05–

0.2 w-% of sorbic acid, between 0.1–

0.5 w-% of benzoic acid, between 0.1–

0.3 w-% of phenols, between 0.1–

0.3 w-% of triclosan, and between 0.01–

0.05 w-% of chlorhexidine, based on the total weight of the formulation;

wherein the agent is selected from corticosteroids and the relative content of corticosteroids is above 0.1 weight-%, relative to total dry mass of the formulation.

2. The formulation according to claim 1, wherein said at least one antioxidant is added in an amount that reduces the increase of oxidation index to less than 100% per 12 months.

3. The formulation according to claim 1, further comprising at least one consistency builder, in an amount that increases the formulation viscosity above that of the non-thickened corresponding formulation to maximally 5 Ns/m² so that spreading over, and retention at, the application area is enabled.

4. The formulation according to claim 3, wherein said at least one consistency builder is added in an amount that increases the formulation viscosity to up to 1 Ns/m².

5. The formulation according to claim 3, wherein the consistency builder is selected from the group consisting of:

pharmaceutically acceptable hydrophilic polymers;

completely synthetic hydrophilic polymers;

natural gums; and

mixtures and further derivatives or co-polymers thereof.

6. The formulation according to claim 5, wherein the polymer weight fractions are in the range between 0.05% and 10%.

7. The formulation according to claim 5, wherein the pharmaceutically acceptable hydrophilic polymers are selected from partially etherified cellulose derivatives, comprising carboxymethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl-, or methyl-cellulose.

8. The formulation according to claim 5, wherein the completely synthetic hydrophilic polymers are selected from polyacrylates, polymethacrylates, poly(hydroxyethyl)-, poly(hydroxypropyl)-, poly(hydroxypropylmethyl)methacrylate, polyacrylonitrile, methallyl-sulphonate, polyethylenes, polyoxiethylenes, polyethylene glycols, polyethylene glycol-lactide, polyethylene glycol-diacrylate, polyvinylpyrrolidone, polyvinyl alcohols, poly(propylmethacrylamide), poly(propylene fumarate-co-ethylene glycol), poloxamers, polyaspartamide, hydrazine cross-linked hyaluronic acid and silicone.

9. The formulation according to claim 5, wherein the natural gums are selected from alginates, carrageenan, guar-gum, gelatine, tragacanth, amidated pectin, xanthan, chitosan collagen and agarose.

10. The formulation according to claim 1, wherein the corticosteroid is selected from the group consisting of:

alclonetasone dipropionate, amcinonide, beclomethasone dipropionate, betamethasone, betamethasone 17-valerate, betamethasone 17,21-divalerate, betamethasone 21-acetate, betamethasone 21-buytrate, betamethasone 21-propionate, betamethasone 21-valerate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortexolone, corticosterone, cortisone, cortisone 17-acetate, 21-deoxybetamethasone, 21-deoxybetamethasone 17-propionate, deoxycorticosterone, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluclorolone acetonide, flumethasone pivalate, fluoconolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, 9-alpha-fluorocortisone, 9-alpha-fluorohydrocortisone, 9-alpha-fluoroprednisolone, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone 17-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-propionate, hydro cortisone 17-valerate, hydrocortisone 21-acetate, hydrocortisone 21-butyrate, hydrocortisone 21-propionate, hydrocortisone 21-valerate, 17-alpha-hydroxyprogesterone, methylprednisolone acetate, mometasone furoate, prednisolone, prednisone, prednisone 17-acetate, prednisone 17-valerate, progesterone, triamcinolone, and trimcinolone acetonide.

11. The formulation according to claim 1, wherein the penetrants are suspended or dispersed in a polar liquid in the form of fluid droplets surrounded by a membrane-like coating of one or several layers, said coating comprising at least two kinds or forms of amphiphilic substances with a tendency to aggregate,

wherein said at least two substances differ by at least a factor of 10 in solubility in said liquid or wherein said substances when in the form of homo-aggregates, for the more soluble substance, or of hetero-aggregates, for any combination of both said substances, have preferred average diameter smaller than the diameter of the homo-aggregates containing merely the less soluble substance;

or

wherein the presence of the more soluble substance lowers the average elastic energy of the membrane-like coating in the vicinity of thermal energy.

12. The formulation according to claim 11, wherein the average penetrant diameter is between 30 nm and 500 nm.

13. The formulation according to claim 11, wherein the average diameter of the penetrant is 2 to 25 times bigger than the average diameter of the pores in the barrier.

14. The formulation according to claim 11, wherein the dry weight of all carrier droplets in a formulation for the use on human or animal skin is 0.01 weight-% (w-%) to 40 w-% of total formulation mass.

15. The formulation according to claim 11, wherein the dry weight of all carrier droplets in a formulation for the use on human or animal mucosa is 0.0001 w-% to 30 w-% of total formulation mass.

16. The formulation according to claim 1, wherein the content of corticosteroids is between 0.1 w-% and 20 w-%.

17. The formulation according to claim 16, wherein the relative content of corticosteroids is the case of clobetasol or one of its derivatives is below 15 w-%, relative to total dry mass of the drug-loaded carriers.

18. The formulation according to claim 16, wherein the content of said corticosteroid is below the saturation maximum, defined as the content of corticosteroid at which the corticosteroid begins to crystallize in or outside the carrier.

19. The formulation according to claim 1, wherein in order to speed up drug action a permeation enhancer is added.

20. The formulation according to claim 1, wherein said corticosteroid is added in an amount which enables the formulation to be applied corresponding to an area dose, as expressed by the total dry mass of penetrant applied per unit area, of between 0.1 mg cm⁻

2 and 15 mg cm<sup>−

2</sup>, if said corticosteroid is desired to exert a therapeutic effect in the deep subcutaneous tissue or the remote tissues, including the whole body.

21. The formulation according to claim 1, wherein said corticosteroid is added in an amount which enables the formulation to be applied with an area dose, as expressed by the total dry mass of penetrant applied per unit area, of between 1 μ

g cm<sup>−

2</sup> and 250 μ

g cm<sup>−

2</sup>, if said corticosteroid is desired to exert a mainly local rather than systemic therapeutic effect.

22. The formulation according to claim 1, wherein consistency and, if necessary other characteristics of the formulation are appropriately selected to enable spraying, smearing, rolling or sponging of the formulation on the application area in particular by using a sprayer, spender, roller or sponge.

23. The formulation according to claim 1, wherein the concentration based on the total weight of the formulation of TBHQ and PG is between 0.005 and 0.2 w-%, of tocopherols is between 0.01 and 0.5 w-%, of ascorbic acid esters is between 0.005 and 0.5 w-%, of ascorbic acid is between 0.005 and 0.5 w-%, of sodium bisulphite or sodium metabisulphite is between 0.005 and 0.5 w-%, of thiourea is between 0.0005 and 0.2 w-%, of cysteine is between 0.05 and 2 w-%, of monothioglycerol is between 0.05 and 2 w-%, of NDGA is between 0.00 1 and 0.2 w-%, of glutathione is between 0.01 and 0.5 w-%, of EDTA is between 0.005 and 0.5 w-%, of citric acid is between 0.005 and 3 w-%.

24. The formulation according to claim 1, wherein the concentration based on the total weight of the formulation of BHA or BHT is between 0.005 and 0.02 w-%, of TBHQ and PG is between 0.01 and 0.02 w-%, of tocopherols is between 0.05 and 0.075 w-%, of ascorbic acid esters is between 0.01 and 0.15 w-%, of ascorbic acid is between 0.01 and 0.1 w-%, of sodium bisulphite or sodium metabisulphite is between 0.01 and 0.15 w-%, of thiourea is between 0.001–

0.01 w-%, of cysteine is between 0.1 and 1.0 w-%, of monothioglycerol is between 0.1 and 1.0 w-%, of NDGA is between 0.005 and 0.02 w-%, of glutathione is between 0.05 and 0.2 w-%, of EDTA is between 0.01 and 0.2 w-%, of citric acid is between 0.01 and 0.2 w-%.

25. The formulation according to claim 1, wherein the concentration based on the total weight of the formulation of thiourea is 0.005 w-%, of cysteine is 0.5 w-%, of monothioglycerol is 0.5 w-%, of NDGA is 0.01 w-%, of glutathione is 0.1 w-%, of EDTA is between 0.05 and 0.975 w-%, of citric acid is between 0.3 and 2 wt-%.

26. The formulation according to claim 1, wherein the bulk concentration based on the total weight of the formulation of ethyl, propyl, butyl or benzyl alcohol is up to 5 w-%.

27. The formulation according to claim 1, wherein the bulk concentration based on the total weight of the formulation of ethyl, propyl, butyl or benzyl alcohol is in the range between 0.5–

3 w.-%.

28. The formulation according to claim 1, wherein the at least one microbiocide is added in an amount that reduces the bacterial count of 1 million germs added per gram of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, after a period of 3 days.

29. The formulation according to claim 1, wherein the tocopherols are selected from tocopheryl-acrylate, -laurate, myristate, -palmitate, -oleate, -linoleate, or any other suitable tolopheryl-lipoate and tocopheryl-POE-succinate.

30. The formulation according to claim 1, wherein the ascorbic acids are selected from 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl, or linoleoyl-L-ascorbic acid.

31. The formulation according to claim 1, wherein the phenols are selected from cresol, 4-chloro-m-cresol, p-chloro-m-xylenol, dichlorophene, hexachlrophene and povidon-iodine.

32. The formulation of claim 1, wherein the corticosteroids are selected from glucocorticoids or mineralocorticosteroids.

33. The formulation according to claim 1, wherein the corticosteroid is propionate.