1. An adhesive formulation for dermal delivery of a drug, comprising:
a) a drug;
b) a solvent vehicle, comprising:
i) a volatile solvent system including at least one volatile solvent, and
ii) a non-volatile solvent system including at least one non-volatile solvent, and
c) at least two solidifying agents,
wherein the formulation has a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, wherein the formulation applied to the skin surface forms a solidified layer after at least partial evaporation of the volatile solvent system, and wherein the drug continues to be dermally delivered after the volatile solvent system is substantially evaporated.
2. A formulation as in claim 1, wherein the non-volatile solvent system acts as a plasticizer for at least one of the at least two solidifying agents.
3. A formulation as in claim 1, wherein the volatile solvent system comprises water.
4. A formulation as in claim 1, wherein one of the at least two solidifying agents increases adhesion of the formulation when applied to a skin surface.
5. A formulation as in claim 4, wherein the solidifying agent which increases adhesion includes at least one member selected from the group consisting of copolymers of methylvinyl ether and maleic anhydride, polyethylene glycol and polyvinyl pyrrolidone, gelatin, low molecular weight polyisobutylene rubber, copolymer of acrylsan alkyloctylacrylamido, aliphatic resins, aromatic resins, polyvinyl pyrrolidone, polyether amide polymers, polyisobutylene rubber, prolamine, monoethyl ester of poly(methyl vinyl ethermaleic acid), monobutyl ester of poly(methyl vinyl ethermaleic acid), free acid form of polymethyl vinyl ethermaleic anhydride copolymer, gelatin, and combinations thereof.
6. A formulation as in claim 1, wherein the at least two solidifying agents are capable of generating higher flux in the solidified layer than either of the solidifying agents alone.
7. A formulation as in claim 1, wherein the volatile solvent system comprises at least one solvent more volatile than water, and includes at least one member selected from the group consisting of ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1, difluoroethane, 1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, cytopentasiloxane, cyclomethicone, methyl ethyl ketone, and combinations thereof.
8. A formulation as in claim 1, wherein the non-volatile solvent system includes at least one member selected from the group consisting of glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, benzoic acid, dibutyl sebecate, diglycerides, dipropylene glycol, eugenol, fatty acids such, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid surfactants, triethyl citrate, 1,2,6-hexanetriol, alkyltriols, alkyldiols, tocopherol, p-propenylanisole, anise oil, apricot oil, dimethyl isosorbide, alkyl glucoside, benzyl alcohol, bees wax, benzyl benzoate, butylene glycol, capryliccapric triglyceride, caramel, cassia oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglycerides, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, diacetin, diacetylated monoglycerides, diethanolamine, diglycerides, ethylene glycol, eucalyptus oil, fat, fatty alcohols, flavors, liquid sugars, ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, limonene, monoacetin, monoglycerides, nutmeg oil, octyldodecanol, orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, vegetable shortening, wax, 2-(2-(octadecyloxy)ethoxy)ethanol, benzyl benzoate, butylated hydroxyanisole, candelilla wax, carnauba wax, ceteareth-20, cetyl alcohol, polyglyceryl, dipolyhydroxy stearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG fatty acid esters, PEG-stearate, PEG-oleate, PEG laurate, PEG fatty acid diesters, PEG-dioleate, PEG-distearate, PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid esters, PEG glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, lanolin, lauric diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, multisterol extract, myristyl alcohol, neutral oil, PEG-octyl phenyl ether, PEG-alkyl ethers, PEG-cetyl ether, PEG-stearyl ether, PEG-sorbitan fatty acid esters, PEG-sorbitan diisosterate, PEG-sorbitan monostearate, propylene glycol fatty acid esters, propylene glycol stearate, propylene glycol, caprylatecaprate, sodium pyrrolidone carboxylate, sorbitol, squalene, stear-o-wet, triglycerides, alkyl aryl polyether alcohols, polyoxyethylene derivatives of sorbitan-ethers, saturated polyglycolyzed C8-C10 glycerides, N-methylpyrrolidone, honey, polyoxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethylformamide, N-methyl formamaide, fatty acid esters, fatty alcohol ethers, alkyl-amides (N,N-dimethylalkylamides), N-methylpyrrolidone related compounds, ethyl oleate, polyglycerized fatty acids, glycerol monooleate, glyceryl monomyristate, glycerol esters of fatty acids, silk amino acids, PPG-3 benzyl ether myristate, Di-PPG2 myreth 10-adipate, honeyquat, sodium pyroglutamic acid, abyssinica oil, dimethicone, macadamia nut oil, limnanthes alba seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, phenyl trimethicone, hydrolyzed wheat protein, and combinations thereof.
9. A formulation as in claim 1, wherein the at least two solidifying agents include at least one member selected from the group consisting of polyvinyl alcohol, esters of polyvinylmethylethermaleic anhydride copolymer, neutral copolymers of butyl methacrylate and methyl methacrylate, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymers, prolamine, pregelatinized starch, ethyl cellulose, fish gelatin, gelatin, acrylatesoctylacrylamide copolymers, ethyl cellulose, hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxy propyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amides, corn starch, pregelatinized corn starch, polyether amides, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate phthalate, ammonia methacrylate, carrageenan, cellulose acetate phthalate aqueous, carboxy polymethylene, cellulose acetate, cellulose polymers, divinyl benzene styrene, ethylene vinyl acetate, silicone, guar gum, guar rosin, gluten, casein, calcium caseinate, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEGPVP, xantham gum, trimethyl siloxysilicate, maleic acidanhydride colymers, polacrilin, poloxamer, polyethylene oxide, poly glactic acidpoly-l-lactic acid, turpene resin, locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol-polyethylene glycol co-polymers, methyacrylic acid-ethyl acrylate copolymers, methacrylic acid or methacrylate based polymers, poly(methacrylic acid), and combinations thereof.
10. A formulation as in claim 1, wherein the drug includes multiple pharmaceutically active agents.
11. A formulation as in claim 1, wherein the drug includes at least one member selected from the group consisting of acyclovir, econazole, miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, and tetracaine, amitriptyline, ketanserin, betamethasone dipropionate, triamcinolone acetonide, clindamycin, benzoyl peroxide, tretinoin, Isotretinoin, clobetasol propionate, halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid, and combinations thereof.
12. A formulation as in claim 1, wherein the drug includes at least one member selected from the group consisting of amorolfine, butenafine, naftifine, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, butoconazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, caspofungin, micafungin, anidulafingin, amphotericin B, AmB, nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, undecylenate, penciclovir, famciclovir, valacyclovir, behenyl alcohol, trifluridine, idoxuridine, cidofovir, gancyclovir, podofilox, podophyllotoxin, ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones, ciproflaxin, bupivacaine, alpha-2 agonists, clonidine, amitriptyline, carbamazepine, alprazolam, ketamine, ketanserin, betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, triamcinolone acetonide, desoximethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate, tacrolimus, picrolimus, tazarotene, isotretinoin, cyclosporin, anthralin, vitamin D3, cholecalciferol, calcitriol, calcipotriol, tacalcitol, calcipotriene, piroxicam, diclofenac, indomethacin, imiquimod, rosiquimod, salicylic acid, alpha hydroxy acids, sulfur, rescorcinol, urea, benzoyl peroxide, allantoin, tretinoin, trichloroacetic acid, lactic acid, benzoic acid, progesterone, norethindrone, norethindroneacetate, desogestrel, drospirenone, ethynodiol diacetate, norelgestromin, norgestimate, levonorgestrel, dl-norgestrel, cyproterone acetate, dydrogesterone, medroxyprogesterone acetate, chlormadinone acetate, megestrol, promegestone, norethisterone, lynestrenol, gestodene, tibolene, testosterone, methyl testosterone, oxandrolone, androstenedione, dihydrotestosterone, estradiol, ethniyl estradiol, estiol, estrone, conjugated estrogens, esterified estrogens, estropipate, and combinations thereof.
13. A formulation as in claim 1, wherein the solidified layer is sufficiently flexible and adhesive to the skin such that when applied to the skin at a human joint, the solidified layer will remain substantially intact on the skin upon bending of the joint.
14. A formulation as in claim 1, wherein the solidified layer is sufficiently flexible and adhesive to the skin such that when applied to a curved skin surface or weight bearing surface on the body, the solidified layer will remain substantially intact on the skin upon bending or stretching of the curved skin surface or weight bearing surface.
15. A formulation as in claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least 2 hours following the formation of the solidified layer, or at least 4 hours following the formation of the solidified layer, or at least 8 hours following the formation of the solidified layer, or at least 12 hours following the formation of the solidified layer.
16. A formulation as in claim 1, wherein the weight ratio of the non-volatile solvent system to the at least two solidifying agents is from about 0.1:1 to about 10:1.
17. A formulation as in claim 1, wherein the solidified layer is formed within about 15 minutes of application to the skin surface under standard skin and ambient conditions.
18. A formulation as in claim 1, wherein the formulation has an initial viscosity prior to skin application from about 100 to about 3,000,000 centipoises, or from about 1,000 to about 1,000,000 centipoises.
19. A formulation as in claim 1, wherein the volatile solvent system is from about 10 wt % to about 85 wt % of the formulation, or from about 20 wt % to about 50 wt % of the formulation.
20. A formulation as in claim 1, wherein the non-volatile solvent system includes multiple non-volatile solvents, and at least one of the non-volatile solvents is capable of improving the compatibility of the non-volatile solvent system with the at least two solidifying agents.
21. A formulation as in claim 1, wherein the at least two solidifying agents together provide enhanced physical stability of the formulation greater than either of the at least two solidifying agents alone.
22. A formulation as in claim 1, wherein the solidified layer is coherent, flexible, and continuous.
23. A formulation as in claim 1, wherein the solidified layer, upon formation, is a soft, coherent solid that is peelable from a skin surface as a single piece or as only a few large pieces relative to the application size.
24. A formulation as in claim 1, wherein the solidified layer, upon formation, is a soft, coherent solid that is easily removed from the skin by washing.
25. A formulation as in claim 1, wherein the solidified layer can be stretched in at least one direction by 5% without cracking, breaking andor separating from a skin surface.
26. A formulation as in claim 1, wherein the solidified layer delivers the drug transdermally.
27. A method of dermally delivering a drug, comprising:
a) applying a formulation as a layer to a skin surface of a subject, the adhesive formulation, comprising:
i) a drug,
ii) a solvent vehicle, comprising:
a volatile solvent system including at least one volatile solvent, and
a non-volatile solvent system including at one non-volatile solvent, wherein the non-volatile solvent system facilitates dermal delivery of the drug at a therapeutically effective rate over a sustained period of time, and
iii) at least two solidifying agents,
wherein the formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system;
b) solidifying the formulation to form a solidified layer on the skin surface by at least partial evaporation of the volatile solvent system; and
c) dermally delivering the drug from the solidified layer to the skin surface at therapeutically effective rates over a sustained period of time.
28. A solidified layer for delivering a drug, comprising:
a) a drug,
b) a non-volatile solvent system comprising at least one non-volatile solvent, wherein the non-volatile solvent system is capable of facilitating the delivery of the drug at therapeutically effective rates over a sustained period of time; and
c) at least two solidifying agents.
29. A solidified layer as in claim 28, wherein the solidified layer has a thickness from about 0.01 mm to about 3 mm.
30. A solidified layer as in claim 28, wherein the solidified layer is adhesive to the skin surface on one side, and is non-adhesive on an opposing side.
31. A solidified layer as in claim 28, wherein the non-volatile solvent system includes multiple non-volatile solvents admixed together which, along with other ingredients in the formulation, forms a solidified layer on the skin not only delivers the drug at therapeutically effective rates but also has acceptable wear properties over a sustained period of time.
32. A solidified layer as in claim 28, wherein the solidified layer is at least substantially devoid of volatile solvents while it dermally delivers the drug, and wherein the volatile solvents include water and any solvent more volatile than water.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A successive-approximation-register (SAR) analog-to-digital converting method, comprising:
generating a first potential by sampling an analog signal;
generating a plurality of output bits sequentially according to the first potential and a plurality of second potentials occurring consecutively on the digital-to-analog converting circuit by using a comparer, wherein the second potentials correspond to the output bits respectively; and
outputting a digital signal based on the output bits,
wherein a step of generating a last output bit of the output bits comprises:
comparing the first potential with a second potential occurring at the last time of the second potentials a plurality of times consecutively by using the comparer, so as to obtain a plurality of first comparison results; and
generating the last output bit according to the first comparison results.
2. The SAR analog-to-digital converting method according to claim 1, wherein the step of generating the last output bit according to the first comparison results comprises:
generating a plurality of digit codes respectively according to the first comparison results of the comparer; and
performing majority decision on the digit codes to obtain the last output bit.
3. The SAR analog-to-digital converting method according to claim 1, wherein the step of generating the corresponding last output bit according to the first comparison results comprises:
generating a plurality of digit codes respectively according to the first comparison results of the comparer; and
performing averaging and round-off on the digit codes to obtain the last output bit.
4. The SAR analog-to-digital converting method according to claim 1, wherein a step of generating each output bit of the last but one output bit to the last but k\u22121 output bit of the output bits comprises:
comparing the first potential with the corresponding second potential a plurality of times consecutively by using the comparer, so as to obtain a plurality of third comparison results;
controlling the digital-to-analog converting circuit according to the third comparison results, so as to adjust the second potential on the digital-to-analog converting circuit; and
generating the corresponding output bit according to the third comparison results,
wherein k is an integer, and k+2 is less than the total sum of the output bits.
5. The SAR analog-to-digital converting method according to claim 4, wherein the step of generating the corresponding output bit according to the third comparison results comprises:
generating a plurality of digit codes respectively according to the third comparison results; and
performing majority decision on the digit codes to obtain the corresponding output bit.
6. The SAR analog-to-digital converting method according to claim 4, wherein the step of generating the corresponding output bit according to the third comparison results comprises:
generating a plurality of digit codes respectively according to the third comparison results; and
performing averaging and round-off on the digit codes to obtain the corresponding output bit.
7. The SAR analog-to-digital converting method according to claim 1, wherein a step of generating each output bit of the rest output bits of the output bits comprises:
comparing the first potential with the corresponding second potential once by using the comparer, so as to obtain a second comparison result;
controlling the digital-to-analog converting circuit according to the second comparison result of the comparer, so as to adjust the second potential on the digital-to-analog converting circuit; and
generating the corresponding output bit according to the second comparison result.
8. A successive-approximation-register (SAR) analog-to-digital converting method, comprising:
generating a first potential by sampling an analog signal;
generating a plurality of output bits sequentially according to the first potential and a plurality of second potentials occurring consecutively on the digital-to-analog converting circuit by using a comparer; and
outputting a digital signal based on the output bits,
wherein a step of generating last j output bits of the output bits comprises:
comparing the first potential with a second potential occurring at the last time of the second potentials a plurality of times consecutively by using the comparer, so as to obtain a plurality of first comparison results respectively; and
generating the last j output bits according to the first comparison results of the comparer, wherein j is an integer greater than 1.
9. The SAR analog-to-digital converting method according to claim 8, wherein the step of generating the last j output bits according to the first comparison results comprises:
generating at least three digit codes respectively according to the first comparison results; and
determining the last j output bits according to the digit codes by using a conversion table.
10. The SAR analog-to-digital converting method according to claim 9, wherein a second potential occurring at the first time to a second potential occurring at the (j\u22121)th time of the second potentials correspond to the first output bit to the (j\u22121)th output bit of the output bits sequentially, a step of generating each output bit of the first output bit to the (j\u22121)th output bit comprises:
comparing the first potential with the corresponding second potential once by using the comparer, so as to obtain a second comparison result;
controlling the digital-to-analog converting circuit according to the second comparison result, so as to adjust the second potential on the digital-to-analog converting circuit; and
generating the corresponding output bit according to the second comparison result.
11. The SAR analog-to-digital converting method according to claim 8, wherein a second potential occurring at the first time to a second potential occurring at the (j\u22121)th time of the second potentials correspond to the first output bit to the (j\u22121)th output bit of the output bits sequentially, a step of generating each output bit of the first output bit to the (j\u22121)th output bit comprises:
comparing the first potential with the corresponding second potential once by using the comparer, so as to obtain a second comparison result;
controlling the digital-to-analog converting circuit according to the second comparison result, so as to adjust the second potential on the digital-to-analog converting circuit; and
generating the corresponding output bit according to the second comparison result.
12. A successive-approximation-register (SAR) analog-to-digital converter (ADC), comprising:
a sampling and digital-to-analog converting circuit, used for generating a first potential by sampling an analog signal;
a comparer, used for comparing the first potential with a second potential on the sampling and digital-to-analog converting circuit a plurality of times consecutively in a last bit determining duration of a plurality of bit determining durations to obtain a plurality of first comparison results respectively, and comparing the first potential with the second potential once individually in the rest bit determining durations to obtain a corresponding second comparison result; and
an SAR control circuit, comprising:
a first determining module, used for generating a group of last output bits according to the first comparison results in the last bit determining duration;
at least one second determining module, wherein each second determining module is corresponding to one of the rest bit determining durations, generates an output bit according to the corresponding second comparison result in the corresponding bit determining duration, and controls the sampling and digital-to-analog converting circuit according to the corresponding second comparison result, so as to adjust the second potential on the sampling and digital-to-analog converting circuit; and
an output logic, used for outputting a digital signal according to the at least one output bit and the group of last output bits.
13. The SAR ADC according to claim 12, wherein the bit number of the group of last output bits is a positive integer, and is less than or equal to the number of comparison times of the comparer.
14. The SAR ADC according to claim 12, wherein the group of last output bits is a last output bit, and the first determining module comprises:
a plurality of generating units, corresponding to the first comparison results respectively, wherein each of the generating units is used for generating a digit code according to the corresponding first comparison result; and
a judging unit, used for performing majority decision on the digit codes to obtain the last output bit.
15. The SAR ADC according to claim 12, wherein the group of last output bits is a last output bit, and the first determining module comprises:
a plurality of generating units, corresponding to the first comparison results respectively, wherein each of the generating units is used for generating a digit code according to the corresponding first comparison result; and
a judging unit, used for performing averaging and round-off on the digit codes to obtain the last output bit.
16. The SAR ADC according to claim 12, wherein the group of last output bits is a plurality of last output bits, and the first determining module comprises:
a plurality of generating units, corresponding to the first comparison results respectively, wherein each of the generating units is used for generating a digit code according to the corresponding first comparison result; and
a judging unit, used for outputting the last output bits according to the digit codes by using a conversion table.
17. The SAR ADC according to claim 12, wherein the comparer is further used for comparing the first potential with the second potential a plurality of times in each bit determining duration of the second bit determining duration to the kth bit determining duration to obtain a plurality of third comparison results individually, and the SAR control circuit further comprises:
at least one third determining module, corresponding to the last but one bit determining duration to the last but k\u22121 bit determining duration respectively, and generating a corresponding output bit according to the third comparison results of the comparer in the corresponding bit determining duration.
18. The SAR ADC according to claim 17, wherein each third determining module comprises:
a plurality of generating units, corresponding to the third comparison results generated in the same bit determining duration respectively, wherein each of the generating units is used for generating a digit code according to the corresponding third comparison result; and
a judging unit, used for performing majority decision on the digit codes to obtain the corresponding output bit.
19. The SAR ADC according to claim 17, wherein each third determining module comprises:
a plurality of generating units, corresponding to the third comparison results generated in the same bit determining duration respectively, wherein each of the generating units is used for generating a digit code according to the corresponding third comparison result; and
a judging unit, used for performing averaging and round-off on the digit codes to obtain the corresponding output bit.