Drug delivery composition containing silyl polymers

Abstract

The invention relates to a silyl-containing polymer that is used, together with a tackifying resin to form an adhesive composition capable of storing and delivering drugs to the skin of a user. Typically the composition is formed into a patch which shows excellent adhesion to the skin even when drugs and other additives are dissolved into the composition.

Claims

1. A composition for drug delivery to a skin comprising: a silyl-containing polymer and at least one drug for drug delivery to the skin; wherein the silyl-containing polymer is cross-linked; wherein the silyl-containing polymer is one or more polyurethane-polyether, and wherein the silyl-containing polymer has a structure as follows: ##STR00011## wherein: R.sup.1 represents a hydrocarbon-based group; R.sup.2 represents an aliphatic or aromatic polyether; R.sup.3 represents a hydrocarbon-based group that comprises 1 to 3 carbon atoms; R.sup.4 and R.sup.5 are each independently selected from a linear or branched alkyl group n is an integer greater than or equal to 0; and p is an integer equal to 0, 1 or 2; wherein n is selected such that the number-average molecular weight of the polymer of formula (I) is greater than 700 Da.

2. The composition according to claim 1, wherein the silyl-containing polymer has two or more silyl groups.

3. The composition according to claim 1, wherein the silyl-containing polymer further comprises a least one group adapted to dissolve or disperse the at least one drug for drug delivery to the skin.

4. The composition according to claim 1, wherein the silyl-containing polymer comprises one or more co-polymers selected form a group consisting of block copolymers, random copolymers, alternating copolymers, and graft copolymers.

5. The composition for drug delivery to the skin comprising: a first component obtainable by reacting the silyl-containing polymer according to claim 1 in the presence of a catalyst; and a second component comprising a drug for drug delivery to the skin.

6. The composition according to claim 1, wherein the drug delivery to the skin is transdermal drug delivery.

7. The composition according to claim 1, wherein the silyl-containing polymer has a weight average molecular weight in the range 700 Da to 250 kDa.

8. The composition according to claim 1, further comprising a tackifying resin.

9. The composition according to claim 8, wherein the tackifying resin is selected from: copolymers comprising at least (meth)acrylic monomers and hydrocarbon monomers; and polymers containing at least one (meth)acrylic function or chain part, and hydrocarbon chain parts.

10. The composition according to claim 8, wherein the tackifying resin is selected from phenol modified terpene resins, hydrocarbon resins, rosin ester resins, acrylic resins and mixtures thereof.

11. The composition according to claim 8, wherein the tackifying resin has a softening point less than or equal to 150° C.

12. The composition according to claim 8, wherein the tackifying resin is selected from: a mixture of styrene-acrylic resins and rosin ester resins; and a dicyclopentadiene-acrylic polymer.

13. The composition according to claim 8, the composition comprising: a) from 20 to 85% by weight of the silyl-containing polymer; and b) from 15 to 80% by weight of the tackifying resin.

14. The composition according to claim 1, further comprising from 0.01 to 3% by weight of at least one catalyst.

15. The composition according to claim 1, wherein the drug has a molecular weight greater than 100 Da.

16. The composition according to claim 1, wherein the drug is for transdermal drug delivery.

17. The composition according to claim 1, wherein the drug is hydrophilic or amphoteric.

18. The composition according to claim 1, wherein the drug is hydrophilic.

19. The composition according to claim 1, wherein the drug is one or more selected from a group consisting of: small molecular drugs, proteins, peptides, enzymes, DNA, RNA, siRNA, antibodies or fragments thereof, vitamins, and minerals.

20. The composition according to claim 1, wherein the drug is selected from the group consisting of: analgesics, anti-inflammatory drugs, hormones, anti-addiction drugs, anti-hypotension drugs, anti-depressants, anti-Alzheimer's drugs, anti-infective, anti-scarring drugs, anti-psychotics, metabolic modulators, pigmentation, nutrients, minerals and vitamins.

21. The composition according to claim 20, wherein the drug is an analgesic.

22. The composition according to claim 21, wherein the analgesic is selected from the group consisting of: isobutylphenylpropanoic acid, capsaicin, isobutylphenylpropanoic acid, flurbiprofen, methyl salicylate, diclofenac epolamine, levomenthol, salicylic acid, ketoprofen, fenbufen, prilocaine, lidocaine, piroxiam, sufentanil, trolamine, or combinations thereof.

23. The composition according to claim 20, wherein the drug is a hormone.

24. The composition according to claim 23, wherein the hormone is selected from: buprenorphine, clobetasone butyrate, clonidine, dexamethasone, diflucortalone valerate, estradiol, estrogen, ethinylestradiol, gestodene, hydrocortisone, levonorgestrel, norelgestromin, norethisterone, prednisolone, teriparatide, testosterone, triamcinolone, or combinations thereof.

25. The composition according to claim 20, wherein the drug is an anti-addiction drug.

26. The composition according to claim 25, wherein the drug is nicotine.

27. A drug delivery patch comprising the composition of claim 1.

28. The drug delivery patch according to claim 27, wherein the patch is a transdermal drug delivery patch.

29. A method, comprising: delivering a drug to skin using a composition comprising a silyl-containing polymer and at least one drug for drug delivery to the skin; wherein the silyl-containing polymer is cross-linked; and wherein the silyl-containing polymer is one or more polyurethane-polyether, and wherein the silyl-containing polymer has a structure as follows: ##STR00012## wherein: R.sup.1 represents a hydrocarbon-based group; R.sup.2 represents an aliphatic or aromatic polyether; R.sup.3 represents a hydrocarbon-based group that comprises 1 to 3 carbon atoms; R.sup.4 and R.sup.5 are each independently selected from a linear or branched alkyl group n is an integer greater than or equal to 0; and p is an integer equal to 0, 1 or 2; wherein n is selected such that the number-average molecular weight of the polymer of formula (I) is greater than 700 Da.

30. The method of claim 29, wherein the composition further comprises a tackifying resin.

31. The method of claim 30, wherein the composition comprises: a) from 20 to 85% by weight of the silyl-containing polymer; and b) from 15 to 80% by weight of the tackifying resin.

32. The method of claim 29, wherein the composition further comprises from 0.01 to 3% by weight of at least one catalyst.

33. The composition according to claim 20, wherein the drug is buprenorphine or clonidine.

Description

SUMMARY OF FIGURES

(1) FIG. 1 shows patches loaded with analgesic drugs (5% w/w). Ibuprofen (A), diclofenac epolamine (B), lidocaine (C) and salicylic acid (D).

(2) FIG. 2 shows the Fenbufen (A) and prilocaine (B) 5% w/w patches.

(3) FIG. 3 shows the Medherant patches loaded with anti-infective compounds. Chlorquinaldol (A), iodine (B), silver nitrate (C) and chlorhexidine (D).

(4) FIG. 4 shows the Medherant nicotine patch 5% w/w.

(5) FIG. 5 shows a typical sample used when measuring the “tack” of an adhesive material.

(6) FIG. 6 shows permeation of NSAIDs and other drugs across Pion® membranes over time from the patch of the present invention.

(7) FIG. 7 shows permeation of steroidal drugs across Pion® membranes over time from the patch of the present invention.

(8) FIG. 8 shows the average load required to peel-off acetate film from pure patches of the invention.

(9) FIG. 9 shows the adhesion of ibuprofen and methyl salicylate patches produced with a grade A composition of the invention.

(10) FIG. 10 shows the adhesion of ibuprofen and methyl salicylate patches produced with a grade B composition of the invention.

(11) FIG. 11 shows adhesion data for a pre-exiting commercial patch (Salonapas patch) against patches of the present invention using grade A and grade B compositions of the invention (coating 10 wt % methyl salicylate).

(12) FIG. 12 shows flux of methyl salicylate and menthol through the Pion® membranes from Salonpas (methyl salicylate 10% w/w and menthol 3% w/w, comparative example) patches compared to patches of the present invention (made from compositions of grade A comprising methyl salicylate 10% w/w and menthol 3% w/w)) over each hour after testing.

(13) FIG. 13 shows total amount of methyl salicylate and menthol permeated across Pion membranes from Salonpas (methyl salicylate 10% w/w and menthol 3% w/w, comparative example) patches compared to patches of the present invention (made from compositions of grade A comprising methyl methyl salicylate 10% w/w and menthol 3% w/w)) over time.

(14) FIG. 14 shows total permeated of nicotine across skin mimicking Strat-M membranes from Niquitin (114 mg) patches compared to patches of the present invention (made from compositions of grade A comprising 49 mg nicotine) over time.

(15) FIG. 15 shows flux of nicotine through skin mimicking Strat-M membranes from Niquitin (114 mg) patches compared to patches of the present invention (made from compositions of grade A comprising 49 mg nicotine) over time.

(16) FIG. 16 shows release of ibuprofen through non-rate limiting Nylon membranes from the patches made using grades F15 (A.1), F16 (A.2) and F17 (A.3).

(17) FIG. 17 shows release of lidocaine through non-rate limiting Nylon membranes from the patches made using grades F15 (A.1), F16 (A.2) and F17 (A.3).

(18) FIG. 18 shows release of methyl salicylate through non-rate limiting Nylon membranes from the patches made using grades F15 (A.1), F16 (A.2) and F17 (A.3).

EXAMPLES

(19) Preparation of the Polymer Component of the Composition

(20) Description of the Compositions:

(21) Desmoseal® XP2636 is a silane-terminated polyether material (covered by formula (I) with n=0) available from the Company Bayer, Germany, with a viscosity of 35,000 mPa.Math.s at 23° C. (according to ASTM standard D1236), and a tensile strength of 0.77 MPa and elongation at break of 133% in tensile test performed according to standard ISO 37 at room temperature.

(22) SPUR® 1050MM is a silane-terminated polyurethane (covered by formula (I) with n different from 0) available from the Company Momentive, Germany, with a viscosity of 35,000 mPa.Math.s at 23° C. (according to ASTM standard D1236), and a tensile strength of 0.68 MPa and elongation at break of 150% in tensile test performed according to standard ISO 37 at room temperature.

(23) XPS 18446 is produced as described in patent application US20110052912 as polymer A (covered by formula (I) with n different from 0) with a final viscosity of about 55,000 mPa.Math.s (according to ASTM standard D1236), and a tensile strength of 0.83 MPa and elongation at break of 230% in tensile test performed according to standard ISO 37 at room temperature.

(24) Poly 15 (silyl-containing polyurethane-polyether and polyurethane-polyester block copolymer, covered by formula (I) with n different from 0) is produced according to the following process:

(25) Step (a3)—Synthesis of a Polyurethane with 2-NCO End Groups and One or More Polyether Blocks:

(26) In a closed reactor of 250 nil, equipped with a stirrer, heating means, thermometer and connected to a vacuum pump was charged 96.89 g of polyether polyol Acclaim® 12200, having a molecular weight in number of 12000 Da, a hydroxyl number of 10 mg KOH/g (corresponding to an equivalent number of —OH functions equal to 0.178 mmol/g). The material is heated to 80° C. and maintained at a reduced pressure of 20 mbar for 1 hour in order to dehydrate the polyether polyol.

(27) Then, 0.1 g of a bismuth carboxylate/zinc catalyst (Borchi Kat® VP0244 available from Borchers GmbH Company) diluted in methyl ethyl ketone solvent at 90% in weight, and 3.01 g of isophorone diisocyanate (containing 37.6% by weight of NCO functions), are introduced into the reactor. The mixture is maintained at atmospheric pressure and heated to 90° C. The quantities introduced thus corresponding to a ratio NCO/OH equal to 1.56. The polyaddition reaction is allowed to last for 3 hours to obtain 100 g of a polyurethane having a NCO function content (followed by potentiometric titration) equal to 9.71 mmol/g, corresponding to the consumption of all hydroxyl functions originating from initial polyether polyol quantity.

(28) Step (b3)—Synthesis of a Polyurethane Block Polyether and Polyester Terminated with —OH Terminal Groups:

(29) 11.52 g of Kuraray® P1010 polyester polyol (having a hydroxyl number of 112 mg KOH/g corresponding to an equivalent OH number function equal to 1.99 mmol/g) is charged in a closed reactor of 250 ml equipped with a stirrer, heating means, thermometer and

(30) connected to a vacuum pump. The material is heated to 80° C. and maintained at a reduced pressure of 20 mbar for 1 hour to dehydrate the polyester polyol. 85.38 g of polyester diol and polyurethane prepolymer obtained in step (a2) is then introduced, thus corresponding to a NCO/OH ratio of 0.6.

(31) The reactor is then maintained under reduced pressure of 20 mbar and heated to 100° C., and polyaddition reaction is progressing for 3 hours until complete consumption of the —NCO polyurethane of step (a2), detected by the progressive disappearing of the NCO peak area by infra-red spectroscopy analysis. This results in 96.9 g of polyurethane with a —OH functions content of 14.74 mmol/g.

(32) Step (c3)—Synthesis of a Polyurethane Block Polyether and Polyester with Alkoxy Silyl Terminal Groups:

(33) 3.1 g of gamma-isocyanato-n-propyl-trimethoxysilane (containing 19.9% by weight of NCO functions) is then introduced into the reactor after step (b2) is completed, leading to a mixture where ratio of NCO/OH functions is equal to 1.

(34) The reactor was then kept under inert atmosphere at 100° C. for 90 minutes until complete reaction occurred, detected by the disappearing of the NCO peak area by infra-red analysis. 100 grams of a polyurethane block polyether and polyester with alkoxy silyl end groups are obtained. Viscosity of this resulting material is measured by a Brookfield RTV viscosimeter at 23° C. and at a speed of 20 rpm with a spindle 6, at 70 000 mPa.Math.s.

(35) Poly 5 (silyl-containing polyurethane). This polymer (covered by formula (II)) is prepared according to the following process:

(36) Step (a2)—Preparation of a Polyurethane (CI) Having —NCO Terminal Groups:

(37) Difunctional polypropylene glycol (PPG) having a molecular weight of 4000 Da and a hydroxyl index equal to 28 mg KOH/g was used as a polyether polyol, and isophorone diisocyanate (IPDI) containing 37.6% w/w of —NCO groups (corresponding to an equivalent number of —NCO functions equal to 8.95 mmol/g) was used as the diisocyanate. In a closed reactor of 250 mL, equipped with a stirrer, heating means, a thermometer and connected to a vacuum pump, 84.89 g of polyether polyol are introduced. The reactor is then heated to 80° C.

(38) and maintained under reduced pressure of 20 mbar for 1 hour in order to dehydrate the polyether polyol.

(39) We introduce in the reactor maintained at atmospheric pressure and heated to 90° C. 4.2 mg of a bismuth/zinc carboxylate catalyst (Borchi® Kat VP0244 from Borchers GmbH Company), and 8.70 g of IPDI (containing 37.6% w/w of —NCO group). The quantities introduced correspond to a NCO/OH ratio equal to 1.8. The polyaddition reaction is continued for 4 hours, until entire consumption of the hydroxyl functions of the poly ether polyol. The NCO-content (expressed in % weight/weight) of the product is followed by a potentiometric titration with an amine, until the aimed value of 1.6% w/w is obtained.

(40) Step (b2): Preparation of the Silyl-Containing Polyurethane “Poly5”;

(41) We introduce in the reactor in the end of step (a1), 6.40 g of gamma-aminosilane Silquest® A1110, corresponding to a ratio NCO/NR6 equal to 1.

(42) The reactor is then maintained under inert atmosphere at 100° C. for 1.5 hours, until complete reaction is achieved (detected by the disappearance of the NCO-band at infrared analysis).

(43) We obtain 100 g of silyl-containing polymer “poly5” having a viscosity at 23° C. measured by a viscosimeter Brookfield RTV equal to 96 Pa.Math.s.

(44) Poly 3 (Silyl-Containing Polyurethane) Covered by Formula (II):

(45) Step (a2) preparation of a polyurethane (A) —NCO end groups:

(46) Voranol® EP1900 having a hydroxyl index equal to 28 mg KOH/g (corresponding to an equivalent number of —OH function equal to 0.50 mmol/g) was used as the polyether polyol, and an IPDI containing 37.6% w/w of —NCO group (corresponding to an equivalent number of —NCO functions equal to 8.95 mmol/g) was used as a diisocyanate.

(47) In a closed reactor of 250 ml, equipped with a stirrer, heating means, thermometer and connected to a vacuum pump was charged 81.85 g of polyether polyol (i.e.: 40.85 mmol of —OH functions). The mixture is heated to 80° C. and maintained at a reduced pressure of 20 mbar for 1 hour to dehydrate the polyether polyol.

(48) Then, we introduce into the reactor maintained at atmospheric pressure and heated to 90° C.:

(49) 0.1 g of a catalyst bismuth/zinc carboxylate (Borchi Kat® VP0244 Borchers GmbH Company) diluted with 90 wt % of MEK and 8.19 g of IPDI (i.e.: 73.32 mmol in NCO— functions).

(50) The quantities introduced thus corresponding to a ratio NCO/OH equal to 1.8. The polyaddition reaction was continued for 4 hours until complete consumption of the hydroxyl groups of the polyether polyol, in order thus to obtain 90.14 g of a polyurethane having —NCO terminal groups, which corresponds to about 32.5 mmol of NCO-functions.

(51) The content of NCO-functions (expressed in % w/w) of the product formed during the reaction is followed by potentiometric titration with an amine, until the target value corresponding to 1.52% is reached.

(52) We then introduce into the reactor, 5.85 g of Unilin® 425 (a linear polymeric monoalcohol of structure C14-054, of IOH=98 mg KOH/g and of melting point=91° C., available from Baker Petrolite), thus corresponding to a NCO/OH ratio equal to 1.44.

(53) The reactor was then kept under inert atmosphere at 100° C. for 1.5 hours until complete reaction is achieved (detected by the disappearance of the NCO-band in the infrared analysis).

(54) This gives 95.98 g of a polyurethane having —NCO terminal group, which represents approximately 22.28 mmol of NCO-functions.

(55) Step (b2) Preparation of Silyl-Containing Polyurethane “Poly3” (Silyl-Containing Polyurethane):

(56) We then introduce into the reactor at the end of step a1), 4 g of aminosilane SILQUEST® A1110 (molecular mass=179 g/mol), thus corresponding to a final NCO/OH ratio equal to 1.

(57) The reactor was then kept under inert atmosphere at 100° C. for 1.5 hours until complete reaction is achieved (detected by the disappearance of the NCO-band in the infrared analysis).

(58) We obtain 100 grams of a silyl-containing polyurethane “poly3”. Its viscosity at 50° C. measured by a Brookfield RTV was 57 Pa.Math.s.

(59) SAX® 510 is a silylated polymer of formula (III) wherein R.sup.3 represents: —(CH.sub.2).sub.3— and R.sup.2 represents a polyether the repeating unit of which is the radical isopropoxy. This polyer is available from Kaneka.

(60) TEGOPAC® BOND 251 is a silylated polymer which is covered by formula (IV) and which is available from Evonik.

(61) Acronal DS3500 is a tackifying resin available from the Company BASF, Germany, comprising methyl acrylate monomers at 91% by weight, and acrylic acid at 9% by weight analyzed by proton and carbon NMR.

(62) Acronal® 4F is a tackifying resin available from the Company BASF, Germany, resulting from polymerization of n-butyl acrylate monomers.

(63) Kolon PX95 is a product from copolymerization of C5-type monomers (68% in weight) with acrylic monomers (acrylic acid 4% in weight, butyl acrylate at 28% in weight analyzed by proton and carbon NMR), available from the Company Kolon Industries, Inc., Korea. It has a softening point of 100° C., an acid number of 20 mg KOH g.sup.−1 according to analysis test standard ASTM D974, and a molecular weight of 720 averaged in number analyzed by gel permeation chromatography. Its viscosity at 100° C. is significantly higher than 100 Pa.Math.s.

(64) Eastman resin described in U.S. Pat. No. 7,332,540 (formulation 1, table 3 column 14) is a tackifying resin produced as described in patent document U.S. Pat. No. 7,332,540. Its features are exhibited in table 3 columns 14 and 15 as being composed by Styrene monomer at 61% in weight, 2-ethylehexylacrylate at 31% in weight, and acrylic acid at 9% in weight. It also contains less than 2% in weigh of diterbutylperoxide. Its softening point is 100° C., and its acid number is 60 mg KOH/g. Its molecular weight in z-average is 15,000 daltons. Its viscosity at 100° C. is significantly higher than 100 Pa.Math.s

(65) 1) Preparation of the Compositions

Example 1 to 14 (Composition Described in Table 1 and Table Ibis)

(66) The compositions that appear in the tables 1, 1bis and 1ter below are prepared by firstly introducing the tackifying resin into a glass reactor under vacuum and heating to around 160° C. Then, once the resin is thoroughly molten, the silane-containing polymer is added.

(67) The mixture is stirred under vacuum for 15 minutes, then cooled to 70° C. The catalyst (K-KAT® 5218) is then introduced. The mixture is kept under vacuum and continues to be stirred for another 10 minutes.

(68) The mixture at lab scale is placed in a cartridge closed with two cups and anti-moisture agents to avoid uncontrolled curing.

(69) TABLE-US-00001 TABLE 1 Compositions (weight %) 1 2 3 4 5 6 7 Dertophene ® 48 H150 Norsolene ® 48 W110 Norsolene ® 48 W80 Sylvalite ® 24 48 RE100 Eastman ® resin Kolon ® 48 33 PX95 Acronal ® 4F 24 Ac Resin ® 15 DS3500 XPS ®18446 50 50 50 50 50 50 50 2-ethylhexyl acrylate monomer acrylic acid melamine formaldehyde ethyl acetate catalyst 2 2 2 2 2 2 2

(70) TABLE-US-00002 TABLE 1bis Compositions (weight %) 8 9 10 11 12 13 14 Dertophene ® 48 48 H150 Sylvalite ® RE100 24 Eastman ® resin 24 Kolon ® PX95 33 33 33 33 Ac Resin ® 15 15 15 15 DS3500 SPUR ® 1050MM 50 50 Desmoscal ® 50 XP2636 “Poly15” 50 “Poly5” 50 “Poly3” 50 50 catalyst 2 2 2 2 2 ? 2

(71) TABLE-US-00003 TABLE 1ter Compositions Weight (%) F15 F16 F17 Sylvalite RE 100 24 24 24 Norsolène W110 24 24 24 Tegopac.sup.R Bond 251 50 SAX.sup.R 510 50 Poly 3 50 Catalyst 2 2 2

(72) 2) Preparation of the tested laminates on PET substrate for technical performance evaluations, said substrates being coated with the cured adhesive composition according to paragraph 1) above, with a coating weight of 20 g/m.sup.2 at laboratory scale. As the support layer, use is made of a rectangular sheet of polyethylene terephthalate (PET) having thickness of 50 urn and dimensions of 20 cm by 40 cm. The composition obtained in 1) is preheated to a temperature close to 100° C. and introduced into a cartridge from which a bead is extruded which is deposited close to the edge of the sheet parallel to its width. The composition contained in this bead is then spread over the entire surface of the sheet, so as to obtain a uniform layer of substantially constant thickness. In order to do this a film spreader (also known as a film applicator) is used, which is moved from the edge of the sheet to the opposite edge. A layer of composition is thus deposited that corresponds to a
weight per unit area of 20 g/m.sup.2, which approximately represents a thickness of the order of 20{circumflex over ( )}m. The thus coated PET sheet is then placed in an oven at 120° C. for 300 seconds for the curing of the composition, then laminated to a protective non-stick layer consisting of a sheet of siliconized film that is rectangular and has the same dimensions. The PET support layer thus obtained is subjected to the tests described below.
180° Peel Test on a Stainless Steel Plate 20 Minutes:

(73) The adhesive strength is evaluated by the 180° peel test on a stainless steel plate as described in FINAT method No. 1 published in the FINAT Technical Manual, 6.sup.th edition, 2001. FINAT is the international federation for self-adhesive label manufacturers and converters. The principle of this test is the following.

(74) A test specimen in the form of a rectangular strip (25 mm×175 mm) is cut from the PET carrier coated with the cured composition obtained previously. This test specimen is, after the preparation thereof, stored for 24 hours at a temperature of 23° C. and in a 50% relative humidity atmosphere. It is then fastened over two-thirds of its length to a substrate constituted of a stainless steel plate. The assembly obtained is left for 20 minutes at room temperature. It is then placed in a tensile testing machine capable, starting from the end of the rectangular strip that is left free, of peeling or debonding the strip at an angle of 180° and with a separation rate of 300 mm per minute. The machine measures the force required to debond the strip under these conditions.

(75) The corresponding results for a coating weight of 20 g/m.sup.2 are expressed in N/cm and are indicated in table 3.

(76) Tack Test (Also Known as Loop Test or Loop Tack Test):

(77) The tack is evaluated by the loop tack test described in FINAT method No. 9, the principle of which is the following.

(78) A test specimen in the form of a rectangular strip (25 mm×175 mm) is cut from the PET carrier coated with the cured composition obtained previously. This test specimen is, after the preparation thereof, stored for 24 hours at a temperature of 23° C. and in a 50% relative humidity atmosphere. The 2 ends of this strip are joined so as to form a loop, the adhesive layer of which is facing outward. The 2 joined ends are placed in the movable jaw of a tensile testing machine capable of imposing a rate of displacement of 300 mm/minute along a vertical axis with the possibility of moving back and forth. The lower part of the loop placed in the vertical position is firstly put into contact with a horizontal glass plate measuring 25 mm by 30 mm over a square area measuring around 25 mm per side. Once this contact has occurred, the displacement direction of the jaw is reversed. The tack is the maximum value of the force needed for the loop to be completely debonded from the plate.

(79) The corresponding results for a coating weight of 20 g/m.sup.2 are expressed in N/cm and are indicated in table 3. The failure profile is also indicated in table 3.

(80) Resistance Time of the Adhesive Joint to Static Shear at 23° C.:

(81) The stability of the adhesive strength of the PET carrier coated with the cured composition is evaluated, no later than one hour after it is obtained, by a test which determines the resistance time of the adhesive joint to static shear at 23° C.

(82) Reference is made, for this test, to the FIN AT method No. 8. The principle is the following. A test specimen in the form of a rectangular strip (25 mm×75 mm) is cut from the PET support layer coated with the cured composition prepared previously. A square portion of 25 mm per side located at the end of the adhesive strip is fastened to a glass plate. The test plate thus obtained is maintained in a vertical position and the strip left free is connected to a weight of 1 kg. Under the effect of this weight, the adhesive joint which ensures the fastening of the strip to the plate is subjected to a shear stress. To better control this stress, the test plate is in fact placed so as to make an angle of 2° relative to the vertical.

(83) The time taken for the strip to debond from the plate following the rupture of the adhesive joint under the effect of this stress is noted. This time is indicated in the table. The corresponding results for a coating weight of 20 g/m.sup.2 are shown in table 3.

(84) Resistance Time of the Adhesive Joint to Static Shear at 90° C.:

(85) The same test as before is performed on the adhesives but the test plate submitted to a weight of 1 kg is maintained at a temperature of 90° C. The results for a coating weight of 20 g/m.sup.2 are shown in table 3.

(86) TABLE-US-00004 TABLE 3 Test results for a coating of 20 g m.sup.−2 Shear resistance Shear Peel 180° C. Loop tack at 90° C. resistance type of type of type of at 23° C. (N/cm) failure (N/cm) failure time failure time 1 6.30 AF 11.02 AF >24 h >24 h 2 0.94 AF 1.38 AF >24 h >24 h 3 0.63 AF 2.13 AF  70 h  14 days 4 2.95 AF 1.97 AF  45 h  18 days 5 1.61 AF 3.98 AF  70 h  11 days 6 2.36 AF 3.86 AF  70 h  8 days 7 3.15 AF 3.35 AF  1 h AF  14 days 9 6.69 AF 10.63 AF >24 h >24 h 10 2.40 AF 4.13 AF  70 h  11 days 11 1.57 AF 2.0 AF >20 min AF  >4 h 12 0.43 AF 1.42 AF  >111 AF  14 days 13 0.53 AF 2.28 AF  >111  14 days 14 1.97 AF 2.76 AF  6 h >24 h AF = adhesive failure
Compositions

(87) Three different grades of composition were employed in solubility experiments: A, B and C (see below). A is the grade which was used for initial studies and further was used as the standard grade for solubility tests.

(88) A is a composition according to example 1 of patent EP2235133 specifically incorporated herein by reference.

(89) B is a composition corresponding to a mixture of equal weights of compositions of each of examples 4 and 5 in European patent EP2336208 specifically incorporated herein by reference.

(90) C is a composition according to example 1 of European patent EP2336208 specifically incorporated herein by reference.

(91) F15 is described in table 1ter, it comprises a polymer according to formula (IV).

(92) F16 is described in table 1ter, it comprises a polymer according to formula (III).

(93) F17 is described in table 1ter, it comprises a polymer according to formula (II).

(94) A major difference between these grades is their viscosity at 100° C. Table 1 summarises properties of these compositions.

(95) TABLE-US-00005 TABLE 1 Properties of compositions Density, Brookfield viscosity at Grade g cm.sup.−3 100° C., mPa S Curing conditions A 1 14000 ± 3000 Oven at 60° C., 100 B 1  7000 ± 3000 mL of water in C 1 15000 ± 4000 vapour phase during F15 1 1600 ± 500 16 hours F16 1  5000 ± 2000 F17 1 2000 ± 500
Typical Patch Preparation Process

(96) A sample of composition is pre-heated to 80° C. in a closed cartridge or inert environment to avoid contact with moisture and approximately 10 ml of the composition is added into a beaker and weighed. A desired quantity of drug, preservative and excipients are then added to the mixture. The mixture is mixed until it has been homogenised and is then cast with the help of a heated Meyer bar onto a release liner. Once cast, the layers of composition are cured at 60° C. in a humid environment during 16 hours.

(97) Drug Release Analysis

(98) In order to determine the drug release profile of the manufactured patches, a pre-cut patch was attached to a membrane (typically Pion, Nylon or Strat-M). The membrane and patch are then placed in a Franz cell and then a PBS pH 7.4 buffer solution is added. Samples are taken at one hour interval for 8 hours. The amount of drug released is calculated using a validated HPLC/UV-Vis method depending on the drug in question. Data for the drug

(99) release properties of the patches of the invention for a range of drugs are shown table 2 and in FIGS. 7 and 8 below.

(100) TABLE-US-00006 TABLE 2 Permeated drug amount. All values are in μg cm.sup.−2 Sample Methyl Salicylic hours Ibuprofen Salicylic Diclofenac acid Caffeine 1 15.46 18.25 0.11 3.38 0.19 2 37.23 24.58 0.16 11.92 2.33 4 73.85 59.78 0.39 31.75 3.26 6 99.60 83.03 0.47 54.71 21.89 Sample Lido- Hydro- hours Ketoprofen caine Prednisolone cortisone Nicotine 1 0.90 16.81 0.06 0.15 2.26 2 4.59 38.49 0.56 0.47 5.05 4 17.37 78.43 1.83 1.08 13.76 6 35.67 110.02 3.54 1.94 18.33
Patch Adhesion Analysis

(101) Three specimens 9 were prepared from a sample 1 as shown in FIG. 5 for each measurement. The specimen 9 has a length 5, a width 15 (around one third the width 7 of the sample 1) and consist of two layers 13. The width 15 was 25.4 mm and the length 5 was 350 mm. A first layer made of adhesive material is provided, attached to a second layer of

(102) back liner, in this case an acetate film having a thickness of 100 μm. The acetate film is attached to the adhesive layer by roll lamination and allowed to rest for 24 hours before

(103) testing. The unbound end 11 of each end of the T-shaped specimen 1 is affixed in a grip (not shown). Each end 11 is aligned correctly to ensure that the tension is applied evenly across the entire specimen 9. The two grips are then drawn apart at a rate of 10 mm min.sup.−1 with a sample rate of 1000 ms. The test was continued until 180 mm of the bonded length 5 was separated. The back liner to which the composition layer was attached in these experiments was a HHlum thick acetate film. The adhesion results for the exemplary compositions are shown below in FIGS. 9 to 12.
Principles of Formulation

(104) In all experiments benzyl alcohol (BenzOH) was employed as a co-solvent. BenzOH is widely used in both pharmaceutical and cosmetic formulations as a preservative, and therefore its addition is required to improve the shelf life of patches. We also found that it reduces viscosity of adhesives allowing a better and faster homogenisation of the polymer/drug mixtures. Additionally, it acts as a solvent for drugs improving their dissolution in the polymer matrix compositions. The total amount of BenzOH in all formulations was in a range of 1-3% w/w.

(105) An amount of drug added to the composition of the invention was calculated to result in 5% w/w concentration in patches. All compounds in the liquid state were added by volume, which was estimated using their specific densities.

(106) Solubility of Analgesic Drugs

(107) Most of the analgesic drugs tested were molecularly soluble in the standard grade (A) 10 composition. Only fenbufen and prilocaine demonstrated poor solubility, and were rather physically dispersed than dissolved. The inventors have found that ibuprofen, ketoprofen, methyl salicylate, salicylic acid, lidocaine and levomenthol are readily soluble in the standard grade. This in turn means that the concentration in patches can easily be increased from 5 to

(108) 30% w/w. Experiments with diclofenac epolamine and piroxicam showed that these 15 compounds have a limited solubility of 5 and ˜2.5% w/w respectively. The data obtained is summarised in Table 3.

(109) TABLE-US-00007 TABLE 3 Solubility of analgesic drugs in compositions. No Drug A Conc., wt % B Conc., wt % 1 Ibuprofen ✓ >5 ✓ >5 2 Methyl salicylate ✓ >5 ✓ >5 3 Diclofenac epolamine ✓ >5 ✓ >5 4 Levomenthol ✓ >5 ✓ >5 5 Salicylic acid ✓ >5 ✓ >5 6 Ketoprofen ✓ >5 ✓ >5 7 Fenbufen x — — — 8 Prilocaine x — — — 9 Lidocaine ✓ >5 ✓ >5 10 Piroxicam ✓   ~2.5 ✓   ~2.5 11 Flurbiprofen ✓ >5 ✓ >5 12 Salsalate ✓ >5 ✓ >5 13 Indomethacin ✓ >5 ✓ >5 14 Aspirin x — — — 15 Paracetamol x — — — 16 Naproxen x — — —

(110) TABLE-US-00008 TABLE 4 List of drugs used in solubility experiments. Solubility in water, No Drug Type Appearance mg mL.sup.−1 1 Ibuprofen Analgesic Solid 0.021 2 Methyl salicylate Liquid 0.690 3 Diclofenac epolamine Solid ~40 4 Levomenthol Solid 0.490 5 Salicylic acid Solid 2.24 6 Ketoprofen Solid 0.051 7 Fenbufen Solid n/a 8 Prilocaine Solid 0.540 9 Lidocaine Solid 0.410 10 Piroxicam Solid 0.023 11 Flurbiprofen Solid 0.025 12 Salsalate Solid 0.246 13 Indomethacin Solid 0.002 14 Aspirin Solid 4.60 15 Paracetamol Solid 14.0 16 Naproxen Solid 0.016 17 Prednisolone Hormone Solid 0.002 18 Hydrocortisone therapy Solid 0.320 19 β-Estradiol Solid 0.004 20 Testosterone Solid 0.023 21 Progesterone Solid 0.009 22 Chlorhexidine Anti- Solid 0.8 23 Iodine infective/ Solid 0.33 24 Silver nitrate parasitic/ Solid soluble 25 Chlorquinaldol fungal/ Solid insoluble 26 Tetracycline biotic Solid 0.231 27 Ivermectin Solid insoluble 28 Nystatin Solid 0.360 29 Praziquantel Solid 0.400 30 Amoxicillin Solid 3.43 31 Penicillin G Solid 0.210 32 Trimethoprim Other Solid 0.400 33 Artesunate Anti- Solid 0.056 34 Artemisinin malaria Solid insoluble 35 Nicotine Other Liquid soluble 36 Cyclosporine Solid insoluble 37 Methotrexate Solid insoluble 38 Salbutamol Solid 14.1 39 Caffeine Solid 21.6 40 Pramipexole Solid 3.9

(111) The grade C composition is the most viscous of the tested samples which limits its application for patch fabrication due to the mixing process. All three grades are identical in 5 terms of drug solubility (tested on ibuprofen, methyl salicylate and levomenthol), but the lower viscosity of A and B makes them preferable for patch fabrication.

(112) Photographs of the patches are displayed on FIG. 1.

(113) It is noted that fenbufen and prilocaine are uniformly distributed in the patch in a form of micro particles, and can potentially be extracted from the patches, despite the incompatibility with compositions and patches of the invention (see FIG. 2.)

(114) Solubility of Drugs for Hormone Therapy

(115) Among tested hormone therapy drugs hydrocortisone showed highest solubility of ˜3.5% w/w. Its mass fraction in Medherant patches is higher than in any commercial analogues such as creams (Cortisone® 1% w/w) and ointments (Efcortelan® 2.5% w/w).

(116) Solubility of Other Drugs

(117) All tested anti-infective drugs were able to mix with each grade (A, B and C) of the compositions of the invention. For example, iodine is freely soluble in corresponding gel compositions up to 5% w/w. It should be noted that the fabrication process has limits related to the size of iodine powder. However, achieved concentration of 5% w/w is higher than in products already available on the market by factor of 5 (Inadine® patches).

(118) Silver nitrate demonstrated good solubility of 2.5% w/w in the compositions and patches of the invention.

(119) Chlorquinaldol showed good dissolution in compositions and patches of the invention. Its concentration in patches can be increased up to 15% w/w without any adverse issues. The concentration can further be increased and represents a substantially improvement over existing commercial analogues (1% w/w Nerisone C® cream).

(120) Chlorhexidine was found to be soluble in compositions and patches of the invention up to ˜3.5% w/w. Despite limited solubility of chlorhexidine, the fabricated patches still contain a higher concentration of the drug in comparison to those existing patches available on the market (Eczmol® 1% w/w, Savlon® 0.1% w/w). Patches containing antiinfective drugs are shown on FIG. 3.

(121) Nicotine was found to be freely soluble in all grades of the compositions and patches of the invention (see FIG. 4). All 5% w/w patches that were produced contained approximately 71 mg of nicotine on area of 21 cm.sup.2. This is a substantial improvement over existing patch systems available on the market which have only 25 mg on a comparable area. If required, the mass fraction of nicotine in Medherant patches can be increased up to 30% w/w.

(122) Obtained solubility data for all tested drugs is summarised in Table 5. We found that 14 out of 19 tested compounds are soluble in compositions and patches of the invention.

(123) TABLE-US-00009 TABLE 5 List of drugs used solubility experiments Max. mass Soluble fraction, No Drug Type in A % Sol. type 1 Ibuprofen Analgesic ✓ 30 Molecular 2 Methyl salicylate ✓ 30 Molecular 3 Diclofenac epolamine ✓ 5 Molecular 4 Levomenthol ✓ 30 Molecular 5 Salicylic acid ✓ 30 Molecular 6 Ketoprofen ✓ 30 Molecular 7 Fenbufen x — Dispersion 8 Prilocaine x — Dispersion 9 Lidocaine ✓ 30 Molecular 10 Piroxicam ✓ 2.5 Molecular 11 Flurbiprofen ✓ 15 Molecular 12 Salsalate ✓ 10 Molecular 13 Indomethacin ✓ 10 Molecular 14 Aspirin x — Dispersion 15 Paracetamol x — Dispersion 16 Naproxen x — Dispersion 17 Prednisolone Hormone x — Dispersion 18 Hydrocortisone therapy ✓ 3.5 Molecular 19 p-Estradiol ✓ 5 Molecular 20 Testosterone ✓ 5 Molecular 21 Progesterone ✓ 15 Molecular 22 Chlorhexidine Anti- ✓ 3.5 Molecular 23 Iodine infective/ ✓ 5 Molecular 24 Silver nitrate parasitic/ ✓ 2.5 Molecular 25 Chlorquinaldol fungal/ ✓ 15 Molecular 26 Tetracycline biotic ✓ 3.5 Molecular 27 Ivermectin ✓ 5 Molecular 28 Nystatin ✓ Molecular 29 Praziquantel ✓ 10 Molecular 30 Amoxicillin x — Dispersion 31 Penicillin G x — Dispersion 32 Trimethoprim x — Dispersion 33 Artesunate Anti- ✓ 6 Molecular 34 Artemisinin malaria ✓ 9 Molecular 35 Nicotine Other ✓ 30 Molecular 36 Cyclosporine ✓ 5 Molecular 37 Methotrexate ✓ 7 Molecular 38 Salbutamol ✓ 5 Molecular 39 Caffeine x — Dispersion 40 Pramipexole x — Dispersion
Typical Nicotine Patch Preparation Process Table List of components used for the synthesis of the nicotine patch

(124) TABLE-US-00010 Scale, Mass fraction, g 100 g.sup.−1 Item No Ingredients wt % 73.0 1 Adhesive 73.0 25.0 2 Nicotine 25.0 2.00 3 Benzyl alcohol 2.00 Preheat Item 1 to 75° C., charge Item 1 into a vessel under nitrogen blanket, subsequently add Items 2 and 3 one by one and heat vessel contents to 75° C. Homogenise at 300 rpm using an overhead stirrer and impeller for a viscous medium for 10 min. Cast the resulting mixture on a release liner and uniformly spread employing a casting instrument. Cure the film in an oven at 90° C. in 50% relative humid atmosphere for 20 min. Apply a backing layer onto the surface upon completion of the curing.
Nicotine Permeation Analysis (Strat-M Membranes):

(125) TABLE-US-00011 Total permeated amount, {circumflex over ( )}g cm−2 Flux, {circumflex over ( )}g cm−2 Sample, h Medherant Niquitin Medherant Niquitin 1 363.7 116.2 363.73 116.16 2 469.6 205.3 152.93 112.95 4 588.0 366.6 59.22 80.63 6 703.4 496.1 57.72 64.74 8 817.2 618.2 56.89 61.08 10 929.7 729.0 56.23 55.40 12 1041.8 840.7 56.07 55.84
Adhesive Grades Used: F15, F16 and F17

(126) TABLE-US-00012 Adhesive Properties F15 F16 F17 Viscosity at 100° C., mPa S 1580 2010 1890 Skinning time/seconds >900 222 631
Drugs Tested: Ibuprofen, Lidocaine, Methyl Salicylate

(127) TABLE-US-00013 Properties/Adhesive Ibuprofen Lidocaine Methyl salicylate Melting point, ° C. 75-77 68   −8.6  LogP 3.97 2.26 2.55 Molecular structure 0
Solubility:

(128) TABLE-US-00014 Adhesive API F15 F16 F17 Ibuprofen ✓ ✓ ✓ Lidocaine ✓ ✓ ✓ Methyl salicylate ✓ ✓ ✓ Skinning time test aim to measure the time needed to create a cured skin on top of a hot adhesive sample. Test is done in a ventilated room at 23° C. with 50% relative humidity. A heated plate is set at 120° C. 5 grams of adhesive is put in an aluminium flat-bed round-shaped
6-cm-diameter tray, and put on the heated plate when the chronometer is started. Every 5 seconds, the cleaned point of a metallic tool (tip of knife blade, screw, paper clip) is put in contact with the surface of adhesive. When removing the point from the surface, it creates a stretching string of soft adhesive. The skinning time is read onto the chronometer when there is no such string, as the surface of the adhesive is hardening and is only slightly
deformed by the point of the tool. This operation is repeated several times, each time with a new sample of the same adhesive material, until the standard deviation of the measurement will be under 20 seconds. The average value of skinning time is then reported.