( 12 ) United States Patent

US010166199B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 166 , 199 B2 Jones et al. ( 45 ) Date of Patent : Jan . 1 , 2019 ( 54 ) TRANSDERMAL PATCH COMPRISING A (58 ) Field of Classification Search ROPIVACAINE FORMULATION None (71 ) Applicant: BUZZZ PHARMACEUTICALS See application file for complete search history . LIMITED , Raheny , Dublin ( IE ) ( 56 ) References Cited ( 72 ) Inventors : Chris Jones , Cardiff GB( ) ; Darren U . S . PATENT DOCUMENTS Green , Cardiff (GB ) 4 , 956 , 171 A * 9 / 1990 Chang ...... A61K 9 / 0014 ( 73 ) Assignee : Buzzz Pharmaceuticals Limited , 424 /448 Dublin (IE ) 9, 295, 655 B2 * 3 /2016 Choi ...... A61K 9/ 7053 (Continued ) ( * ) Notice: Subject to any disclaimer , the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U . S . C . 154 ( b ) by 0 days . EP 1661560 5 /2006 (21 ) Appl. No. : 15 /027 , 905 EP 1964552 9 / 2008 ( Continued ) ( 22 ) PCT Filed : Oct. 7 , 2014 ( 86 ) PCT No .: PCT/ EP2014 /071437 OTHER PUBLICATIONS $ 371 (c )( 1 ), Merriam Webster definition of oil ( obtained online May 25, 2017 ). * ( 2 ) Date : Apr. 7 , 2016 (Continued ) ( 87 ) PCT Pub . No .: W02015 /052183 Primary Examiner — Robert A Wax PCT Pub. Date : Apr. 16 , 2015 Assistant Examiner — Melissa S Mercier (74 ) Attorney , Agent, or Firm - Barnes & Thornburg , (65 ) Prior Publication Data LLP US 2016 /0235689 A1 Aug. 18 , 2016 (57 ) ABSTRACT (30 ) Foreign Application Priority Data The present invention relates to a transdermal patch com prising a pharmaceutical formulation , the formulation com Oct . 7 , 2013 (EP ) ...... 1317718 prising ropivacaine or an opioid , a pharmaceutically -accept able adhesive and optionally one or more excipients selected (51 ) Int. CI. from the group consisting of carrier oils , penetration enhanc A61K 9 / 70 ( 2006 .01 ) ers and hydrophilic materials . The present invention also A61K 47 / 10 ( 2017 .01 ) relates to methods of preparation of such a pharmaceutical (Continued ) formulation , as well as the use of such a transdermal patch (52 ) U . S . CI. in the treatment of pain ( e . g . nociceptive and/ or neuropathic CPC ...... A61K 9 / 7061 ( 2013 . 01 ) ; A61K 31/ 445 pain ). (2013 .01 ) ; A61K 31/ 485 (2013 .01 ) ; ( Continued ) 19 Claims, 13 Drawing Sheets

cremeriahan 1 ml saturated ropivacaine in pH5 . 5 wens 3 % Ropivacaine patch in 900A 5 % Ropivacaine patch in 2074 87 . 5 % Ropivacaine patch in 2074 V 10 % Ropivacaine patch in 2074 Ropivacainepermeated(ug/cm2) * 25% Ropivacaine patch in 2677 izatea. 7 . 5 % Ropivacaine patch in 2677 a halbmw 1 ml saturated ropivacaine in H20

12 24 36 48 Time ( h ) US 10 ,166 , 199 B2 Page 2

(51 ) Int . CI. WO WO2007070679 6 / 2007 A61K 31/ 445 ( 2006 .01 ) WO WO2007100910 9 / 2007 A61K 47 / 14 ( 2017 . 01 ) WO WO2011005853 1 / 2011 A61K 31/ 485 ( 2006 . 01 ) WO WO2011 / 121082 Al 10 / 2011 A61K 47 /22 ( 2006 .01 ) WO WO2016009063 AL 1/ 2016 (52 ) U . S . CI. CPC ...... A61K 47 / 10 (2013 . 01 ) ; A61K 47/ 14 OTHER PUBLICATIONS ( 2013. 01 ); A61K 47 / 22 ( 2013 .01 ) PCT Search Report and Written Opinion for PCT /EP2014 /071437 , completed Nov . 19 , 2014 . ( 56 ) References Cited GB Search Report for GB1317718 . 3 , completed Apr. 8 , 2014 . U . S . PATENT DOCUMENTS Power, I. , “ An Update on Analgesics; ” 2011 ; British Journal of Anaesthesia ; 107 , ( 1 ); pp . 19 - 24 . 2002 / 0197284 Al 12 / 2002 Luo et al . Cilurzo , F . , “ Adhesive properties: a critical issue in transdermal 2004 / 0096491 A1 5 / 2004 Tateishi et al. patch development, ” 2012 , Expert Opin . Drug Deliv . 9 ( 1 ) :33 - 45 . 2005 / 0087195 AL 4 / 2005 Huang Roy et al. “ Transdermal delivery of buprenorphine through cadaver 2005 /0276842 Al 12 / 2005 Zhang et al. skin ” Journal of Pharmaceutical Sciences , vol . 83 , No. 2 , 1994 , pp . 2007 / 0059351 A1 3 / 2007 Murrell et al. 126 - 130 . 2007 /0189978 A1 * 8 / 2007 Zhang ...... * * * * A61K 9 / 0014 424 /45 Taghizadeh et al. “ Preparation and In Vitro Evaluation of a New 2010 /0008991 A11 / 2010 Mantelle Fentanyl Patch Based on Acrylic /Silicone Pressure - Sensitive Adhe 2011/ 0104093 A1 * 5 / 2011 McLaughlin ...... A61K 8 /60 sive Blends” Drug Development and Industrial Pharmacy , vol. 35 , 424 / 70 . 11 No. 4 , 2009 , pp . 487 -498 . 2013 /0072884 Al * 3 / 2013 Hamlin ...... A61K 9 / 703 Liao et al. “ In Vitro Skin Permeation of Buprenorphine Transdermal 604 / 304 Patch ” Journal of Food and Drug Analysis , vol. 16 , No . 6 , 2008 , pp . 8 - 15 . Roy et al. “ Controlled transdermal delivery of fentanyl: Character FOREIGN PATENT DOCUMENTS izations of pressure - sensitive adhesives for matrix patch design ” EP 2177217 AL 4 / 2010 Journal of Pharmaceutical Sciences , vol. 85 , No . 5 , 1996 , pp . EP 2687205 1 / 2014 491 - 495 . EP 2759294 7 / 2014 WO WO2005123046 12 / 2005 * cited by examiner U . S . Patent Jan . 1 , 2019 Sheet 1 of 13 US 10 , 166 , 199 B2

70 T 1ml saturated ropivacaine in pH5 . 5 tamoyka3 % Ropivacaine patch in 900A + sanoin 5 % Ropivacaine patch in 2074 7. 5 % Ropivacaine patch in 2074 secunoastem 10 % Ropivacaine patch in 2074 Ropivacainepermeated(ug/cm2) casamenwensen 5 % Ropivacaine patch in 2677 se 7 . 5 % Ropivacaine patch in 2677 BS 1ml saturated ropivacaine in H2O

wwwMob 12 36 Time (h ) Figure 1 U . S . Patent Jan . 1 , 2019 Sheet 2 of 13 US 10 , 166 , 199 B2

1ml saturated ropivacaine in buffer pH 10 . 4 + strength 7 . 5 % ropivacaine in 2677 selen 7 . 5 % ropivacaine ( 5 % transcutol) in 2677 Ropivacainepermeated(ug/cm2) sono 4 % ropivacaine in 900A une inste 12 % Ropivacaine patch in 2074

TASYSHAKERS RIETAVAS O tePROP i 24 48 Time (h ) Figure 2 U . S . Patent Jan . 1 , 2019 Sheet 3 of 13 US 10 , 166 , 199 B2

sucede 7 .5 % ropivacaine , 15 % [30 /60 / 10 ] (PG /cap 90 /Brij 93 ) in 2677 1 + elektromos 7 . 5 % ropivacaine in 2677 Ropivacainepermeated(ug/cm2)

-to + 24 36 48 Time ( h ) Figure 3 U . S . Patent Jan . 1 , 2019 Sheet 4 of 13 US 10 , 166 , 199 B2

and insenen 7 . 5 % ropivacaine , 15 % [ 25 /60 / 10 / 5 ] (PG / CAP 90 / Brij 93 / Tween 80 ) in 2677 (b / n : 200213b ) H - - 7 . 5 % ropivacaine, 15 % [ 25 /60 / 10 / 5 ] ( PG / CAP 90 / Brij 93 /Cremphor EL) in 2677 ( b / n : 2002130) + men 7 . 5 % ropivacaine , 15 % [80 / 13. 3 / 6 . 7 ] (CAP 90 /Brij 93/ Tween 80 ) in 2677 ( b / n : - 200213e ) + - 7 .5 % ropivacaine , 15 % [66 . 7 / 11. 1 /22 . 2 ] (CAP 90 /Brij 93 /Tween 80 ) in 2677 (b /n - 200213h ) +

Ropivacainepermeated(ug/cm2) +

o 24 36 Time ( h ) Figure 4 atent Jan . 1 , 2019 Sheet 5 of 13 US 10 , 166 , 199 B2

6 .5 % ropivacaine, 35 % [ 30 /60 / 10 ] ( PG / cap 90 /Brij 93 ) in 2677 ( b / n : 250313a ) esetleges 6 .5 % ropivacaine , 5 % transcutol, 20 % [ 30 /60 / 10 ] (PG / cap 90 /Brij 93 ) in 2677 ( b / n : 0404130 ) + camerele 7 . 5 % ropivacaine, 15 % [ 30 /60 / 10 ] (PG / cap 90 / Brij 93 ) in Ropivacainepermeated(ug/cm2) 2677 (b / n : 040213b )

12 24 36 48 Time ( h ) Figure 5 U . S . Patent Jan . 1 , 2019 Sheet 6 of 13 US 10 , 166 , 199 B2

2000

1800 annelijamo lidocaine saturated H2O

1600 dhuropivacaine saturated H2O

Amountpermeated(ug/cm2)

400 +

- 200 +

- ONES ANTERNER + SE X X A S SARAKSTS ARE MADERA EL MES LES FESTES CASESONGERASKANsamaa KESELAMATAS PERS mutassa . O 4 8 12 Time (h . ) 1620 Figure 6 U . S . Patent Jan . 1 , 2019 Sheet 7 of 13 US 10 , 166 , 199 B2

audio maa ropivacaine saturated H2O H 5- 7 . 5 % ropivacaine patch (bn : AH 011012 )

XWENSIYADARE Ropivacainepermeated(ug/cm2) A

+ O 4 8 12 16 20 24 28 32 36 40 44 48 Time (h ) Figure 7 U . S . Patent Jan . 1 , 2019 Sheet 8 of 13 US 10 , 166 , 199 B2

condimm 4 % Ropivacaine in 900A ( b / n : 041212b ) ( n = 6 )

Ropivacainepermeated(ug/cm2)

-to + 4 8 12 162024 Time ( h ) Figure 8 U . S . Patent Jan . 1 , 2019 Sheet 9 of 13 US 10 , 166 , 199 B2

Ropivacaineflux(ug/cm2h)

and Ropivacaine in 900A ( b / n : 041212b ) ( n = 6 )

+ 4 8 12 162024 Time ( h ) Figure 9 U . S . Patent Jan . 1 , 2019 Sheet 10 of 13 US 10 , 166 , 199 B2

se sasa 7 . 5 % Ropivacaine, 15 % [ 30 /60 / 10 ] ( PG /Capryol 90 / Brij 93 in 2677 ( b / n : 040213b ) ( n = 6 ) sunset 7 . 5 % ropivacaine in 2677 patch (bn : 011012 ) (n = 6 )

Ropivacainepermeated(ug/cm2) EAA

+ 4812162024 Time ( h ) Figure 10 U . S . Patent Jan . 1 , 2019 Sheet 11 of 13 US 10 , 166 , 199 B2

4 . 5 , semuanythose 7 . 5 % Ropivacaine , 15 % [ 30 / 60 / 10 ] ( PG / Capryol 90 / Brij 93 in 2677 ( b /n : 040213b ) ( n = 6 ) HM Ropivacaineflux(ug/cm2h)

+ +

o + 8 12 162024 Time ( h ) Figure 11 U . S . Patent Jan . 1 , 2019 Sheet 12 of 13 US 10 , 166 , 199 B2

140 Tsunadime 6 . 5 % ropivacaine , 35 % [ 30 /60 / 10 ] PG / Capryol 90 / Brij 93 in 2677 ( b / n : 250313a ) Sensations 6 . 5 % ropivacaine, 5 % menthol, 20 % [ 30 /60 / 10 ] PG / Capryol 90 / Brij 93 in 2677 ( b / n : 150413a - 1 ) englannen 5 % Lidocaine , Versatis ( b / n : 346D01 )

Ropivacainepermeated(ug/cm2)

RISTA

SENAW

+ 8 0 12 162024 Time ( h ) Figure 12 U .S . Patentatent Jan . 1 , 2019 Sheet 13 of 13 US 10 , 166 , 199 B2

x GURU SOSIS Ropivacaineflux(ug/cm2h) NISASI KERANA +

XXX + S

- + ELEPAS conglom 6 . 5 % ropivacaine, 35 % [ 30 /60 / 10 ] PG / Capryol - 90 / Brij 93 in 2677 ( b / n : 250313a ) 6 . 5 % ropivacaine , 5 % menthol, 20 % [ 30 /60 / 10 ] + PG /Capryol 90 / Brij 93 in 2677 ( b / n : 150413a - 1 )

- nam pasur 5 % Lidocaine, Versatis ( b / n : 346D01)

+ + o 4 12 2 16 20 24 Time ( h ) Figure 13 US 10 , 166 , 199 B2 TRANSDERMAL PATCH COMPRISING A In certain conditions, the pain may be caused by a ROPIVACAINE FORMULATION complex mixture of nociceptive and neuropathic factors . For example , myofascial pain is understood to result from noci CROSS -REFERENCE TO RELATED ceptive input from muscles. It is , however , plausible that APPLICATIONS 5 such abnormal muscle activity is itself the result of neuro pathic conditions . In both neuropathic and nociceptive disease types, neu This application is a U .S . national phase of PCT/ EP2014 / rons become unusually sensitive and develop spontaneous 071437 , filed on Oct. 7 , 2014 , which claims priority to activity , abnormal excitability , and a heightened sensitivity European Patent Application No . 1317718 .3 , filed on Oct . 7 , 10 to chemical, thermal and mechanical stimuli . This phenom 2013 . The disclosures of both European Patent Application enon is known as “ peripheral sensitization ” . Localized No . 1317718 . 3 and PCT Application No. PCT/ EP2014 / delivery of anaesthetic can afford a method of desensitizing 071437 are hereby incorporated herein by reference in their the aberrant stimuli . entireties. Lidocaine (often referred to as lignocaine ) is widely used 15 as a local anaesthetic , and is commercially available in both FIELD OF THE INVENTION an injectable form and as a transdermal patch . When com pared with a systemic dose , transdermal delivery of local The present invention relates to a novel formulation . anaesthetics provides prolonged anaesthesia at the target site More specifically , the present invention relates to a novel for pain suppression , and involves reduced plasma levels , anaesthetic or analgesic formulation suitable for transdermal 20 hence a reduced potential toxicity . administration . Such formulations are suitable for the topical However , in spite of the widespread use of lignocaine treatment of neuropathic and / or nociceptive pain . The pres transdermal patches , there remains a need for improved ent invention also relates to processes for the preparation of transdermal anaesthetic formulations . the formulations defined herein , as well as to the use of these In addition , there remains a need for improved analgesic formulations for the topical treatment of neuropathic and /or 25 transdermal patch formulations to provide analgesia , in nociceptive pain . particular improved patches for the delivery of opioid anal gesics . BACKGROUND OF THE INVENTION There is also a need for transdermal formulations having good skin penetration properties . Moreover , there is a need Nociceptive pain is pain generated from nociceptors 30 for transdermal formulations of anaesthetic or analgesic responding to stimuli by sending nerve signals to the spinal agents that exhibit improved drug potency and having a cord and brain . Such signals may be indicative of tissue longer duration of action for reducing the occurrence of irritation , impending injury, or actual injury , and are often breakthrough pain . characterized as aching and /or direct pains . Examples of Aspects of the invention were devised with the foregoing conditions associated with nociceptive pain include bone 35 in mind . fractures, burns, bumps, bruises, inflammation ( from an infection or arthritic disorder ), arthralgia , general myalgia SUMMARY OF THE INVENTION and more specific myalgia caused by symptoms categorized generally as amplified musculoskeletal pain (AMP ) syn The present invention provides a novel pharmaceutical drome . 40 formulation suitable for topical application for the treatment Neuropathic pain is pain caused by damage or disease that of pain , for example nociceptive and / or neuropathic pain . affects the somatosensory system . Neuropathic pain is the Thus, according to a first aspect of the invention , there is result of an injury or malfunction in the peripheral or central provided a transdermal patch comprising a pharmaceutical nervous system . The pain is often triggered by an injury , but formulation , said formulation comprising ropivacaine or an it is not necessary for such an injury to involve actual 45 opioid and a pharmaceutically -acceptable adhesive , and damage to the central nervous system . Nerves can be infil - wherein said formulation has an in vitro permeation rate trated or compressed by tumours , strangulated by scar tissue, or inflamed by infection . The pain is typically characterized In another aspect , the present invention provides a trans by burning , lancinating , coldness or so - called pins - and dermal patch comprising a pharmaceutical formulation , said needles -type sensations . Persistent allodynia - pain result - 50 formulation comprising : ing from a non -painful stimulus such as a light touch — is ( i) ropivacaine or an opioid , also a common characteristic of neuropathic pain . The pain ( ii ) a pharmaceutically - acceptable adhesive , and option itself may have continuous and / or episodic (paroxysmal ally ( iii ) one or more of either a penetration enhancer , a components , the having electric shock - like qualities . The hydrophilic material, and a carrier oil having a ropiva pain may persist for months or years beyond the apparent 55 caine or an opioid solubility of greater than or equal to healing of any damaged tissue . In these scenarios, such pain 1 . 5 % ( w / w ) . signals no longer represent an alarm about ongoing or In another aspect, the present invention provides a phar impending injury, rather it is the alarm system itself that is maceutical formulation suitable for inclusion into a trans malfunctioning . Common causes of painful peripheral neu dermal patch as herein defined , said formulation comprising ropathies are herpes zoster, infection , HIV -related neuropa - 60 ropivacaine or an opioid and a pharmaceutically -acceptable thies , nutritional deficiencies , toxins , remote manifestations adhesive , and wherein said formulation has an in vitro of malignancies , immune mediated disorders and physical human skin permeation rate greater than 1 . 8 ug cm - 2 h - 1 . trauma to a nerve trunk . Neuropathic pain is also common In another aspect, the present invention provides a phar in cases of cancer, either as a direct result of a cancer on maceutical formulation comprising : peripheral nerves ( for example through compression by a 65 ( i ) ropivacaine or an opioid , tumour ), or as a side effect of chemotherapy radiation , injury ( ii ) a pharmaceutically -acceptable adhesive, and option or surgery . ally US 10 , 166 , 199 B2

( iii ) one or more of either a penetration enhancer, a exhibit significantly poorer skin permeation characteristics hydrophilic material , and a carrier oil having a ropiva than lidocaine saturated H2O ( see FIG . 6 ) , thereby present caine or an opioid solubility of greater than or equal to ing a considerable barrier to transdermal patch development. 1 . 5 % ( w / w ) . When used in conjunction with the present invention , wherein said formulation is suitable for inclusion into a 5 ropivacaine may be present in its free base form , or as a salt . transdermal patch as herein defined . Suitably , when used as part of the pharmaceutical formula In another aspect, the present invention provides a phar tion described herein , ropivacaine is present in its free base maceutical formulation or transdermal patch as herein form , since it is commonly understood that the skin is defined for use as a medicament. typically more permeable to uncharged lipophilic per In another aspect, the present invention provides a phar - 10 meants , as opposed to charged species . The free base form maceutical formulation or transdermal patch as herein would also be expected to be more soluble in typical defined for use in the treatment of pain (e .g . neuropathic pharmaceutical adhesives than would a salt form ( e. g. ropi and / or nociceptive pain ). vacaine HCI) . In another aspect, the present invention provides a method The amount of ropivacaine present in the pharmaceutical of treating pain ( e . g . neuropathic and / or nociceptive pain ), 15 formulation of the present invention will depend on how said method comprising topically administering to a human soluble it is in the pharmaceutically - acceptable adhesive and or animal subject in need of such treatment a therapeutically excipients present. Typically , the ropivacaine will present at effective amount of a pharmaceutical formulation as defined an amount of 3 - 20 % w / w . herein , or applying a transdermal patch as herein defined . In one embodiment, the amount of ropivacaine is between In another aspect , the present invention provides a method 20 3 and 10 % w / w . of preparing a pharmaceutical formulation as defined herein , Suitably , the amount of ropivacaine is between 6 and 8 % said method comprising mixing : w / w . ( i ) ropivacaine or an opioid , Opioid Analgesiscs (ii ) an adhesive as defined herein , and optionally The transdermal patches of the present invention may ( iii ) one or more of a penetration enhancer as defined 25 comprise an opioid analgesic . Any suitable opioid analgesic herein , a hydrophilic material as defined herein and a may be used . carrier oil as herein defined and having a ropivacaine or In an embodiment, the opioid analgesic is selected from an opioid solubility of greater than or equal to 1. 5 % morphine, codeine , thebaine, diacetylmorphine (morphine ( w / w ) . diacetate ; heroin ), nicomorphine (morphine dinicotinate ) , 30 dipropanoylmorphine (morphine dipropionate ) , desomor DETAILED DESCRIPTION OF THE phine , acetylpropionylmorphine, dibenzoylmorphine , INVENTION diacetyldihydromorphine, hydromorphone, hydrocodone , oxycodone, oxymorphone, ethylmorphine and buprenor Ropivacaine phine , fentanyl, pethidine , levorphanol, methadone , trama Ropivacaine , chemical name (2S ) - N - ( 2 , 6 - dimethylphe - 35 dol and dextropropoxyphene . nyl) - 1 - propyl- 2 -piperidinecarboxamide and having the The amount of opioid present in the pharmaceutical structure shown below , is an aminoamide containing an formulation of the present invention will depend on how asymmetric carbon atom , and is produced as the single S soluble it is in the pharmaceutically -acceptable adhesive and enantiomer for clinical use as local anaesthetic . excipients present. Typically , the opioid will present at an 40 amount of 3 - 20 % w / w . In one embodiment, the amount of opioid is between 3 and 10 % w / w . Suitably , the amount of opioid is between 6 and 8 % w / w . Transdermal Patch H3C 45 Despite the poor in vitro skin penetration observed with a saturated solution of ropivacaine when compared to a satu HN rated solution of lidocaine ( see FIG . 6 ), it has surprisingly been found that it is possible to prepare a transdermal H3C CH3 delivery system for ropivacaine . 50 The transdermal patches of the present invention are prepared by casting a wet pharmaceutical formulation layer as described herein at a known thickness onto a suitable release liner . In its simplest form , the pharmaceutical for Studies focussing on the use of local anaesthetic during mulation may comprise ropivacaine or an opioid and a cataract surgery have demonstrated that dose - for - dose , ropi- 55 pharmaceutically - acceptable adhesive. The pharmaceutical vacaine may be as much as four times as potent as lidocaine formulation may additionally comprise one or more addi anaesthetics . In this study , the use of ropivacaine was tional excipients, including a carrier oil, penetration enhanc preferred to lidocaine due to its longer half life , which ers and hydrophilic materials . Typically , the pharmaceutical contributed to a reduction in levels of breakthrough pain . formulation are cast at a wet thickness of between about 240 In view of the above advantages, ropivacaine presents a 60 um to about 550 um , to provide a dry thickness of between suitable candidate for inclusion into a transdermal patch for about 45 um and about 95 um , suitably between about 80 um the treatment of pain , such as nociceptive and neuropathic and about 85 um . After casting, the layer is dried , and then pain . In theory , such advantages would allow for a trans - laminated with a backing membrane . A suitable container or dermal patch having improved drug potency and enhanced closure system may be used protect the transdermal patch drug persistence characteristics. 65 during transportation and storage . However , in spite of the advantages discussed above , Suitable backing membranes may be occlusive or non ropivacaine saturated H2O has been demonstrated to be occlusive. Where a non -occlusive backing membrane is US 10 , 166 , 199 B2 used , it is desirable to use a fully occlusive container or only recorded for those patches that remained free of ropi closure system to prevent degradation of the cast pharma- vacaine or opioid precipitation ( i . e . those that were below ceutical formulation layer prior to use . The backing mem - saturation concentration ). brane may be of any thickness , but is suitably between about The present invention also provides a pharmaceutical 10 to 260 um thick . Suitable materials include , but are not 5 formulation , said formulation comprising ropivacaine or limited to , synthetic polymers including, for example , poly - opioid and a pharmaceutically -acceptable adhesive , and esters , polycarbonates , polyimides , polyethylene, poly ( eth - wherein said formulation has an in vitro human skin per ylene terphthalate ), polypropylene , polyurethanes and poly - meation rate of ropivacaine or opioid that is greater than 1 . 8 vinylchlorides . The backing membrane may also be a ug cm - 2 h - ? . laminate comprising additional layers that may include By in vitro human skin permeation rate we mean the rate vapour deposited metal, such as aluminium , additional syn - of delivery of ropivacaine or opioid through human epider thetic polymers , and other materials, to enable a heat seal, mal membranes at time periods up to 12 hours . such as EVA copolymer . Suitably , the backing membrane Suitably , the in vitro human skin permeation rate of comprises occlusive Scotchpak 9730® obtainable from 3M . 16 ropivacaine or opioid is the apparent steady state flux The release liner is typically disposed on an opposite ( calculated from the approximately linear portion of the surface of the pharmaceutical formulation layer to the back cumulative permeation profile ), typically observed between ing membrane and provides a removable protective or 3 and 12 hours , or between 4 and 12 hours , when assessed impermeable layer, usually but not necessarily rendered under the conditions detailed in the following sections . non - stick so as to not adhere to the pharmaceutical formu- 20 In an embodiment , the in vitro human skin permeation lation layer. The release liner serves to protect the pharma rate of ropivacaine or opioid is between 1. 8 ug cm -2 h - 1 and ceutical formulation layer during storage and transit , and is 10 ug cm - 2 h - ?. intended to be removed during use . The release liner may be In a further embodiment , the in vitro human skin perme formed from the same materials used for the backing mem - ation rate of ropivacaine or opioid is between 2 ug cm h brane, but may be formed from metal foils , Mylari , poly - 25 and 6 ug cm - 2 h - ? . ethylene terephthalate , siliconized polyester, fumed silica in In a further embodiment, the in vitro human skin perme silicone rubber, polytretrafluoroethylene , cellophane , sili - ation rate of ropivacaine or opioid is between 3 ug cm - 2h - 1 conized paper , aluminized paper , polyvinyl chloride film , and 5 ug cm -2h - 1. composite foils or films containing polyester such as poly - Pharmaceutical -Acceptable Adhesive ester terephthalate , polyester or aluminized polyester, poly - 30 The pharmaceutically - acceptable adhesive is selected tetrafluoroethylene, polyether block amide copolymers , both in terms of its ability to solubilise ropivacaine or an polyethylene methyl methacrylate block copolymers , poly - opioid , and its adhesive tack and peel properties. urethanes, polyvinylidene chloride , nylon , silicone elasto - In one embodiment, the adhesive has a ropivacaine or mers , rubber- based polyisobutylene , styrene, styrene -buta - opioid solubility in excess of 2 . 5 % w / w at room tempera diene , and styrene - isoprene copolymers , polyethylene , and 35 ture . polypropylene . Any suitable adhesive may be used . In an embodiment, Suitably, the release liner is an occlusive or semi- occlu - the adhesive is selected from acrylate/ polyacrylate materi sive backing film being compatible with the pharmaceuti - als , rubbers and silicones. Suitably, the adhesive is an cally -acceptable adhesive present in the pharmaceutical for acrylate or polyacrylate material, including acrylate copo mulation layer. 40 lymers and acrylate - vinyl acetate , such as Duro - Tak Suitably , the release liner may be selected from Scotchpak 87 - 2677® , Duro - Tak 87 -900A® , Duro - Tak 87 -2074® , 9741® , Scotchpak 1022® , Scotchpak 9742® , Scotchpak Duro - Tak 87 - 2054® , Duro - Tak 87 - 2052® , Duro - Tak 9744® , Scotchpak 9748® and Scotchpak 9755® , all of 87 -2196® , obtainable from Henkel. which are obtainable from 3M and comprise fluoropolymers In another embodiment, the adhesive is selected from coated onto polypropylene or polyester film . Other suitable 45 Duro - Tak 87 -900A® , Duro - Tak 87- 2677® and Duro - Tak release liners made by other manufacturers may also be 87 - 2074® , having approximately 4 % ( w / w ) , 8 % ( w / w ) and used . The release liner may be of any thickness known in the 12 % (w /w ) ropivacaine solubility respectively and exhibit art. Suitably the release liner has a thickness of about 0 .01 ing excellent peel and tack performance . mm to about 2 mm . Suitably , the adhesive is Duro - Tak 87 - 2677® . In one embodiment, the release liner is Scotchpak 9741® . 50 In one embodiment, a suitable volatile solvent is added to In another embodiment, the release liner is Scotchpak the adhesive to reduce viscosity and aid solvation . Suitable 1022® . solvents may include , but are not limited to , isopropyl The container or closure system may be made from a alcohol, methanol, ethanol and ethyl acetate . range of materials suitable for protecting the packaged Typically, the amount of adhesive is between 58 and 97 % transdermal patch from moisture and light. 55 w / w . Permeation Rate of Ropivacaine or Opioid Carrier Oil As previously stated , the present invention provides a The carrier oil is selected both for its compatibility with transdermal patch comprising a pharmaceutical formulation , the pharmaceutically - acceptable adhesive and for its ability said formulation comprising ropivacaine or an opioid and a to solubilise ropivacaine or the opioid . Carrier oils used in pharmaceutically - acceptable adhesive , and wherein said for - 60 conjunction with the present invention include, but are not mulation has an in vitro human skin permeation rate of limited to , sorbitan monooleate , sorbitan trioleate , triglyc ropivacaine or opioid that is greater than 1 . 8 ug cm - 2 h - ? . erides of carprylic / capric acid , propylene glycol dicaprylate / The permeation of ropivacaine or opioid through human dicaprate , ethoxy diglycol, propylene glycol monocaprylate , skin has been measured for selected patches and saturated glycerol monooleate , lanolin , acetylated lanolin , polyethyl solutions . Permeation / release measurements of ropivacaine 65 ene glycol lanolin , glycerol monocaprylate / caprate , propyl or opioid through a 9 % EVA membrane were used as a tool ene glycol laurate , and/ or mono - or diglycerides of capric to select candidate patches . Permeation /release data was acid . US 10 , 166 , 199 B2 Suitably, the carrier oil has a water solubility of less than In another embodiment, the penetration enhancer is 0 .1 % ( w /w ) and a ropivacaine or opioid solubility in excess included in the pharmaceutical formulation as part of a of 3 % ( w / w ) . binary mixture including either a carrier oil or a hydrophilic Suitably , the carrier oil may be sorbitan trioleate , propyl- material. ene glycol monocaprylate , glycerolmonocaprylate / caprate , 5 Suitably , the penetration enhancer is included in the propylene glycol laurate , and /or mono - or diglycerides of pharmaceutical formulation as part of a ternary mixture capric acid . Suitably , the carrier oil is present in the phar- including both a carrier oil and a hydrophilic material. maceutical formulation at a concentration of between about In another embodiment, the penetration enhancer is 2 . 5 % ( w / w ) and about 35 % ( w / w ) . included in the pharmaceutical formulation as part of a In one embodiment, the carrier oil is in an amount of 10 quaternary mixture including a carrier oil , a hydrophilic between 9 and 21 % w / w . material , and an additive selected from non - ionic surfac Suitably , the carrier oil is in an amount of between 12 and tants , hydrophilic surfactants , terpenes (such as menthol) 21 % w / w . and membrane disruptors, including those obtainable under Suitably , the carrier oil has a ropivacaine or opioid is the trade names Transcutol® , Brij 98® , Tween 80® , and solubility in excess of 4 % ( w / w ) . Cremphor EL® . Suitably , the carrier oil may be propylene glycol mono - Hydrophilic Material caprylate , propylene glycol laurate and /or mono - or diglyc - The hydrophilic materials used in conjunction with the erides of capric acid . Even more suitably , the carrier oil is present invention may aid the skin absorption of the ropi propylene glycol monocaprylate , obtainable under the trade 20 vacaine or opioid . The hydrophilic material may be present name Capryol 90® . as a polar enhancer, and is liquid at skin temperature . In one embodiment, the carrier oil is included in the Suitably , the hydrophilic material and the quantities in which pharmaceutical formulation without any other excipients . it is added should be non - toxic , non - irritating , non -aller Suitably , the carrier oil is included in the pharmaceutical genic , odourless , tasteless , colourless , soluble, and compat formulation as part of a ternary mixture including both a 25 ible with the ropivacaine or opioid and the other excipients penetration enhancer and a hydrophilic material. herein described . In another embodiment, the carrier oil is included in the In one embodiment , the hydrophilic material will have a pharmaceutical formulation as part of a quaternary mixture hydrophilic - lipophilic balance (HLB ) of greater than 7 . including a penetration enhancer, a hydrophilic material, and Examples of hydrophilic materials suitable for inclusion into an additive selected from non -ionic surfactants , hydrophilicir 330 the pharmaceutical formulation of the present invention surfactants, terpenes and dual membrane disruptors , includ include , but are not limited to , propylene glycol, glycerol, ing those obtainable under the trade names Transcutol® , polyethylene glycol, short chain water soluble esters of citric Brij® 98® , Tween 80® , Cremphor EL® and menthol. acid , acetic acid , hexylene glycol and alcohols , including Penetration Enhancer diols and polyols . Suitably, when used , the hydrophilic The penetration enhancers used in conjunction with the 35 material is present in the pharmaceutical formulation at a present invention serve to promote the percutaneous absorp - concentration( w / w ). of between about 1 . 5 % ( w / w ) and about 20 % tion of ropivacaine or opioid by temporarily diminishing the Suitably , the hydrophilic material is in an amount of impermeability of the skin . Importantly , when included in between 6 and 11 % w / w . the pharmaceutical formulations of the present invention , 40 Suitably , the hydrophilic material is propylene glycol. the penetration enhancer must not compromise the release in an embodiment, the hydrophilic material is included in characteristics of the adhesive . the pharmaceutical formulation as part of a binary mixture Suitably, the penetration enhancer and the quantities in including either a carrier oil or a penetration enhancer . which it is added should be non - toxic , non - irritating , non - Suitably , the hydrophilic material is included in the phar allergenic , odourless , tasteless , colourless , soluble , and com - 45 maceutical formulation as part of a ternary mixture includ patible with ropivacaine or the opioid and the other excipi - ing both a carrier oil and a penetration enhancer . ents herein described . Importantly , the enhancer should not In another embodiment, the hydrophilic material is lead to the loss of bodily fluids , electrolytes and other included in the pharmaceutical formulation as part of a endogenous materials , and skin should immediately regain quaternary mixture including a carrier oil , a penetration tion 50 enhancer, and an additive selected from non - ionic surfac its barrier properties on its removal. Examples of penetration 30 tants , hydrophilic surfactants , terpenes (such as menthol) enhancers suitable for inclusion into the pharmaceutical and membrane disruptors , including those materials obtain formulation of the present invention include , but are not able under the trade names Transcutol® , Brij 98® , Tween limited to , sugar fatty acid esters and ethers , C . - C , fatty 80® , and Cremphor EL? . alcohol , azone, oleic ethers , terpenes and ethoxy ethanols· . 55 Excipient Combinations Suitably , when used , the penetration enhancer is present in As indicated in the foregoing paragraphs , the pharmaceu the pharmaceutical formulation at a concentration of tical formulations of the present invention optionally com between about 1 . 4 % ( w / w ) and about 15 % ( w / w ) . prise one or more excipients in addition to the ropivacaine Suitably , the penetration enhancer is in an amount of or opioid and the pharmaceutically -acceptable adhesive . between 1 . 5 and 4 % w / w . 60 Suitably , the pharmaceutical formulation comprises two Suitably, the penetration enhancer may be polyoxyethyl - excipients present as a binary mixture and , more suitably , the ene oleyl ether, obtainable under the trade name Brij 93® , or pharmaceutical formulation comprises three excipients pres 2 - ( 2 - ethoxyethoxy ) ethanol, obtainable under the trade name ent as a ternary mixture . Transcutol® , or menthol. It has been demonstrated that for pharmaceutical formu In one embodiment, the penetration enhancer is included 65 lations containing ternary mixtures of excipients , improved in the pharmaceutical formulation without any other excipi- transdermal delivery of ropivacaine or an opioid may be ents . achieved . US 10 , 166 , 199 B2 10 The binary or ternary mixtures may improve the trans Suitably , the binary mixture comprises propylene glycol dermal delivery of the ropivacaine or opioid by temporary monocaprylate , obtainable under the trade name Capryol alteration of the skin barrier function , or by improvements in 90® , and propylene glycol . drug /skin partitioning resulting from increased solubility of Ternary Mixtures the drug in the stratum corneum . The selection of binary / 5 The ternary mixtures for use in conjunction with the ternary / quaternary mixtures is designed to maintain reason - present invention contain a carrier oil, a penetration able solubility of the ropivacaine or opioid in the pharma- enhancer and a hydrophilic material. ceutically - acceptable adhesive . It is not necessary for the In one embodiment, the quantity of ternary mixture pres binary / ternary / quaternary mixture to increase drug solubility ent in the pharmaceutical formulations is from about 10 % in the pharmaceutically - acceptable adhesive. In certain 10 ( w / w ) to about 40 % ( w / w ) , suitably from about 15 % ( w / w ) embodiments the solubility of the ropivacaine or opioid in to about 35 % ( w / w ) , and more suitably about 35 % (w / w ) . the selected ternary mixtures of excipients is greater than the Optionally , the ternary mixture may contain one or more solubility of the ropivacaine or opioid in each individual additives , selected from the group consisting of non - ionic excipient. In such embodiments , the observed solubility is surfactants , hydrophilic surfactants , terpenes ( such as men significantly greater than the predicted solubility based upon 15 thol) and membrane disruptors . Suitable additives include, proportional contributions from the solubilities in individual but are not limited to those obtainable under the trade names excipients , suggesting a significant cooperative effect on Transcutol® , Brij 98® , Tween 80® , and Cremphor EL? . drug solubility . In one embodiment, the ternary mixture comprises a The inclusion of one or both of a penetration enhancer carrier oil selected from the group consisting of propylene and / or a hydrophilic material in the binary or ternary mix - 20 glycol monocaprylate , propylene glycol laurate and /or tures may contribute to improving transdermal ropivacaine mono - or diglycerides of capric acid ; a penetration enhancer or opioid delivery by increasing skin permeation according selected from the group consisting of polyoxyethylene oleyl to the mechanisms discussed in the preceding paragraphs. ether , obtainable under the trade name Brij 93® , or 2 -( 2 Binary Mixtures ethoxyethoxyethanol, obtainable under the trade name The binary mixtures for use in conjunction with the 25 Transcutol® ; and a hydrophilic material selected from the present invention contain two excipients selected from a group consisting of propylene glycol, glycerol, polyethylene carrier oil, a penetration enhancer and / or a hydrophilic glycol, short chain water soluble esters of citric acid , acetic material. acid , hexylene glycol and alcohols , including diols and In one embodiment, the quantity of binary mixture pres polyols . ent in the pharmaceutical formulations is from about 5 % 30 Suitably , the ternary mixture comprises propylene glycol ( w / w ) to about 40 % ( w / w ) . Suitably , from about 10 % ( w / w ) monocaprylate , obtainable under the trade name Capryol to about 35 % ( w /w ) . 90® ; polyoxyethylene oleyl ether, obtainable under the trade Optionally , the binary mixture may contain one or more name Brij 93® ; and propylene glycol. additives , selected from the group consisting of non - ionic Preparation of Pharmaceutical Formulations surfactants , hydrophilic surfactants , terpenes (such as men - 35 The pharmaceutical formulations of the present invention thol) and membrane disruptors . Suitable additives include , can be prepared using conventional techniques known in the but are not limited to those obtainable under the trade names art . Transcutol® , Brij 98® , Tween 80® , and Cremphor EL® . The pharmaceutical formulations are suitably prepared by In one embodiment, the binary mixture comprises a mixing all of the components together. penetration enhancer selected from the group consisting of 40 The individual components may be mixed by simply polyoxyethylene oleyl ether, obtainable under the trade adding all of the components at the same time into a mixing name Brij 93® , or 2 - ( 2 - ethoxyethoxy ) ethanol, obtainable vessel and then mixing them all together (a " one - pot" under the trade name Transcutol® , and a hydrophilic mate - mixture ). Alternatively, the components may be added rial selected from the group consisting of propylene glycol, sequentially in two or more steps or stages . Suitably, where glycerol, polyethylene glycol, short chain water soluble 45 more than one excipient forms part of the formulation , such esters of citric acid , acetic acid , hexylene glycol and alco - excipients may be pre -mixed to form binary or ternary hols , including diols and polyols . excipient mixtures, which may themselves be subsequently In another embodiment, the binary mixture comprises a mixed with the other components of the formulation . carrier oil selected from the group consisting of propylene Other experimental conditions required to prepare the glycol monocaprylate , propylene glycol laurate and /or 50 formulations of the present invention , such as mixing times, mono - or diglycerides of capric acid , and a penetration mixing equipment, temperature control etc . can be readily enhancer selected from the group consisting of polyoxyeth - determined by a person of ordinary skill in the art . ylene oleyl ether, obtainable under the trade name Brij 93® , Further experimental details will also be evident from the or 2 - ( 2 -ethoxyethoxy ) ethanol, obtainable under the trade accompanying Examples. name Transcutol® . 55 Once prepared , the pharmaceutical formulations of the Suitably, the binary mixture comprises propylene glycol present invention are formed into a transdermal patch for monocaprylate, obtainable under the trade name Capryol topical application . 90® , and polyoxyethylene oleyl ether, obtainable under the Therapeutic Uses trade name Brij 93® . The pharmaceutical formulations of the present invention In another embodiment, the binary mixture comprises a 60 are particularly suited to the treatment of pain . Once admin carrier oil selected from the group consisting of propylene istered , the transdermal patch comprising the pharmaceuti glycol monocaprylate, propylene glycol laurate and /or cal formulation provides a localised delivery of the ropiva mono - or diglycerides of capric acid , and a hydrophilic caine or opioid , thus providing pain relief at a desired material selected from the group consisting of propylene location . During localised delivery, quantities of the ropi glycol , glycerol, polyethylene glycol , short chain water 65 vacaine or opioid may be absorbed into the patient' s blood soluble esters of citric acid , acetic acid , hexylene glycol and stream , thereby providing an additional, systemic delivery of alcohols , including diols and polyols . the anaesthetic . US 10 , 166 , 199 B2 12 Types of pain that can be treated with the transdermal FIG . 5 compares the permeation , over 48 hours , of patch of the present invention include nociceptive and ropivacaine from various transdermal patches of the present neuropathic pain . invention , using continuous EVA (3M 9702 ) membrane . Nociceptive pain may be pain associated with tissue FIG . 6 compares the in vitro human skin permeation irritation , impending injury , or actual injury , and is often 5 properties of a saturated ropivacaine solution versus those of characterized as aching and /or direct pains. Examples of a saturated lignocaine solution . conditions associated with nociceptive pain include bone FIG . 7 compares the in vitro human skin permeation , over fractures, burns . bumps . bruises, inflammation ( from an 48 hours , of ropivacaine from a patch containing 7 . 5 % infection or arthritic disorder ), arthralgia , general myalgia ( w / w ) ropivacaine in Duro - Tak® 87 - 2677 adhesive , with a orized 10 simple ropivacaine -saturated solution . and more specific myalgia caused by symptoms categorized S FIG . 8 demonstrates the in vitro human skin permeation , generally as amplified musculoskeletal pain (AMP ) syn over 48 hours , of ropivacaine from a patch containing 4 % drome . ( w / w ) ropivacaine in Duro - Tak® 87 - 900A adhesive . Neuropathic pain is pain caused by damage or disease that FIG . 9 demonstrates the mid time- point flux (ug /cm² h - 1) affects the somatosensory system . The pain is typically 1515 of ropivacaine for a 4 % ( w / w ) ropivacaine in Duro - Tak® characterized by burning , lancinating, coldness or so - called 87 - 900A transdermal patch . pins - and -needles - type sensations. Persistent allodynia FIG . 10 compares the in vitro human skin permeation , pain resulting from a non - painful stimulus such as a light over 24 hours , of ropivacaine from a patch containing 7 . 5 % touch — is also a common characteristic of neuropathic pain . ( w /w ) ropivacaine in Duro - Tak® 87 -2677 adhesive , with an The pain itself may have continuous and / or episodic (par - 20 identical patch containing 15 % ( w / w ) of a ternary propylene oxysmal) components , the having electric shock - like quali - glycol, Capryol® 90 , Brij® 93 (30 /60 / 10 ) excipientmixture . ties . Common causes of painful peripheral neuropathies that FIG . 11 demonstrates the mid time- point flux (ug /cm²h - ?) can be treated with the transdermal patches of the present of ropivacaine for a transdermal patch containing 7 . 5 % invention include herpes zoster, infection , HIV - related neu ( w / w ) ropivacaine and 15 % (w / w ) of a ternary propylene ropathies , nutritional deficiencies , toxins , remote manifes - 25 glycol, Capryol® 90 , Brij® 93 ( 30 /60 / 10 ) excipient mixture tations of malignancies , immune mediated disorders and in Duro - Tak® 87 - 2677 adhesive . physical trauma to a nerve trunk . Neuropathic pain is also FIG . 12 compares the in vitro human skin permeation , common in cases of cancer, either as a direct result of a over 24 hours , of ropivacaine from various transdermal cancer on peripheral nerves ( for example through compres - patches of the present invention , with a commercially sion by a tumour ) , or as a side effect of chemotherapy 30 available lidocaine transdermal patch ( Verstatis ). radiation , injury or surgery . FIG . 13 compares the mid time- point flux (ug / cm² h - - ) of The transdermal patches of the present invention may also ropivacaine for various transdermal patches of the present prove effective in cases where the pain is be caused by a invention , with that of lidocaine from a commercially complex mixture of nociceptive and neuropathic factors, for available lidocaine transdermal patch (Verstatis ). example, myofascial pain . 35 The pharmaceutical compositions of the present invention EXAMPLES may be used on their own as the sole therapy. Alternatively, the compositions may be administered as part of a combi Solubility Assessment nation therapy with one or more other pain treatments or anaesthetics . Such conjoint treatment may be achieved by 40 Adhesive Only Patches way of the simultaneous, sequential or separate administra Initial solubility was assessed visually in the wet adhesive tion of the individual components of the treatment. prior to casting . Only mixtures where the drug had fully dissolved were cast. Mixtures were cast onto a suitable DETAILED DESCRIPTION OF THE DRAWINGS release liner and dried prior to laminating with an occlusive 45 backing membrane , with a small portion being laminated The present invention is further defined with reference to with release liner . This provided a section of patch that could the accompanying figures , in which data are presented as easily be prepared for microscopic evaluation ( via transfer to mean - standard error (SE ) , and where : a glass slide ) . Solubility in the dried adhesive mixture was FIG . 1 compares the permeation , over 48 hours , of assessed visually and by polarised microscopy . The presence ropivacaine from a variety of transdermal patches of the 50 of precipitate indicated that the drug loading was above present invention , with a ropivacaine saturated aqueous saturation . solution and a ropivacaine saturated citrate acetate buffer Duro - Takx adhesives 87 - 2677 , 87 - 900A and 87 -2074 solution at pH 5 , using continuous EVA (3M 9702 ) mem - were chosen as lead adhesives based on their solubility for brane. ropivacaine . The solubilities were 27 . 5 < 10 % ( w / w ) , > 4 < 5 % FIG . 2 compares the permeation , over 48 hours , of 55 ( w / w ) and 212 < 14 % (w /w ) respectively, as indicated in ropivacaine from a variety of transdermal patches of the Table 1 below : present invention , with a ropivacaine saturated aqueous solution using continuous EVA ( 3M 9702) membrane . TABLE 1 FIG . 3 compares the permeation , over 48 hours , of ropivacaine from a simple ropivacaine - in - adhesive (Duro - 60 Selected pharmaceutically -acceptable adhesives Tak® 87 - 2677) patch , with one containing 15 % ( w / w ) of a and their solubility ( % w / w ) for ropivacaine ternary propylene glycol , Capryol® 90 , Brij® 93 ( 30 /60 / 10 ) Apparent excipient mixture , using continuous EVA ( 3M 9702 ) mem Functional Chemical % ropivacaine brane . Adhesive groups composition solids solubility ( % ) FIG . 4 compares the permeation , over 48 hours , of 65 DURO - TAK None acrylate 43 . 88 4 < 5 % ropivacaine from various transdermal patches of the present 87 - 900A copolymer invention , using continuous EVA ( 3M 9702 ) membrane . US 10 , 166 , 199 B2 13 14 TABLE 1 -continued TABLE 2 - continued Selected pharmaceutically -acceptable adhesives Ropivacaine solubility ( % w / v ) in candidate excipients and their solubility ( % w / w ) for ropivacaine Excipient Chemical name HLB % Solubility Apparent Crodamol EO ethyl oleate 11 0 . 5 - 1 . 2 Functional Chemical % ropivacaine PEG 200 Poly ( ethylene glycol) < 1 Adhesive groups composition solids solubility ( % ) PEG 300 Poly ( ethylene glycol) < 1 DURO - TAK COOH acrylate 38 .68 27. 5 < 10 % HLB - Hydrophilic - lipophilic balance 87 - 2677 vinylacetate 10 acrylate Further excipients were assessed for ropivacaine solubil DURO - TAK COOH/ — OH 28 . 38 212 < 14 % ity and compatibility with Duro - Tak® adhesive 87 - 900A . 87 - 2074 Adhesive compatibility was assessed by mixing ropivacaine ( 4 % ( w / w ) ) and excipient ( 5 % ( w / w ) ) with Duro - Tak® Solubility Enhancement with Excipients 87 - 900A . Mixtures that were miscible were cast at a wet 15 thickness of 350 um onto 3M 9741 release liner , and then Combinations of adhesive and individual, or mixtures of, dried and laminated with 3M 9730 occlusive backing mem excipients were studied with a view to improve the solubility brane . Successful castings demonstrated no precipitate after of ropivacaine , and therefore possibly increase its delivery 72 hours . Adhesive -compatible excipients were then sub rate from the transdermal patch . Moreover, the inclusion of jected to solubility testing according to the protocol one or more excipients in the pharmaceutical formulation , described above, see Table 3 below : TABLE 3 Ropivacaine solubility ( % w / v ) in candidate excipients , showing compatibility with Duro - Tak ® 87 - 900A 900A Excipient Chemical name HLB Compatible % Solubility Span 80 sorbitan monooleate 4 . 3 no Span 85 sorbitan trioleate 1 . 8 yes 3 . 1 - 3 . 9 Captex 355 triglycerides of caprylic /capric acid – yes 0 .2 - 1 . 2 Labrafac PG propylene glycol yes 1 . 3 - 1 . 8 dicaprylate /dicaprate Transcutol P ethoxy diglycol 4 . 2 yes 4 . 1 - 4 . 6 Capryol 90 propylene glycolmonocaprylate 6 yes 6 . 3 - 7 . 4 Capmul - GMO- 50 glycerol monooleate 3 - 4 no Medilan - SO - (RB ) lanolin 4 no Modulan acetylated lanolin - no Solulan - 75 PEG - 75 lanolin . no Capmul -MCM - EP glycerol monocaprylate /caprate 5 - 6 not 4 . 5 - 5 . 1 assessed * Lauroglycol 90 propylene glycol laurate 5 not 3 . 7 - 4 . 7 assessed * Capmul -MCM - C8 - mono/ diglycerides capric acid 5 - 6 not 5 . 5 - 6 .0 EP assessed * * compatibility with Duro - Tak ® 87- 900A not assessed at this stage due to higher observed solubility in Capryol 90 HLB - Hydrophilic - lipophilic balance 45 including penetration enhancers and hydrophilic materials , The ropivacaine solubilities of binary and ternary mix was advantageous for the purpose of enhancing skin pen tures of excipients were studied in order to improve etration . ropivacaine delivery . Furthermore , it was desirous to incor A series of excipients were selected for ropivacaine solu - 50 porate the skin permeation properties of more than one bility investigation , as seen in Table 2 below . Approximate solubilities were assessed visually by gradual addition of excipient ropivacaine to a known volume of excipient at room tem Binary mixtures of Capryol 90® and Transcutol® — 25 / perature until saturation was observed . 75 , 50 / 50 , 75 / 25 ( % v / v ) — were prepared and exhibited ropivacaine solubilities of 23. 6 < 4 .8 % ( w / v ) , 24 .6 < 5 .6 % TABLE 2 (w /v ) and 24 .6 < 5. 2 % (w / v) respectively . Ropivacaine solubility ( % w / v ) in candidate excipients Other binary and ternary mixtures of propylene glycol , Excipient Chemical name HLB % Solubility 60 CapiyorCapryol 90® and Brij 93® seen in Table 4 were prepared on a w /w basis and stirred with an excess of ropivacaine in 20 IPM isopropylmyristate 11 . 5 0 . 7 - 1 . 4 Labrafil M 1944 CS apricot kernel oil PEG - 6 4 1 . 2 - 2 . 1 ml vials for approximately 24 hours at room temperature . esters Aliquots of each mixture were then centrifuged , filtered , DMI dimethylisosorbide 2 . 8 - 3 . 6 Tween 80 polyethylene glycol sorbitan 15 < 0 . 12 65 diluted ( 1 / 5000 ) with 50 / 50 acetonitrile and water , and monooleate analysed by HPLC . The ropivacaine solubilities of the binary and ternary mixtures are shown in Table 4 below : US 10 , 166 , 199 B2 15 16 TABLE 4 with 3M 9730 occlusive polyester film laminate . Patches incorporating menthol were cast at lower wet thickness , Ropivacaine solubility ( % w / v ) in binary and ternary typically 240 -400 um , and suitably 240 um . These films excipient mixtures prepared on a w / w or w / w / w basis were dried for 1 hour at room temperature , then for either 5 Mixture % PG % capryol 90 % Brij 93 % solubility 5 or 10 minutes at 50° C . Suitably the patches were dried at 100 . 0 1 .93 50° C . for 5 minutes. Dry films ranged from 45 to 78 um , 100 . 0 5 . 87 suitably about 45 um . Thinner films subjected to shorter 100 . 0 1 . 83 drying times at50° C . greatly reduced the loss of the volatile 34 . 0 33 . 1 32 . 8 4 .81 79 . 9 20 . 1 2 . 97 menthol component. The films incorporating menthol were 79 . 9 20 . 1 5 . 42 10 laminated with 3M 9730 occlusive polyester film laminate . 50 . 0 50 . 0 5 .65 Film thicknesses were measured using a digital microm 59 . 8 19 . 8 20 . 3 4 .42 20 . 1 59 . 8 20 . 0 5 . 93 eter. Patch thickness was measured at five locations and the AwN0OvauAWNA 40 . 4 39 . 7 19 . 8 5 . 36 thickness of release liner /backing membrane was measured 59 . 9 30 . 0 10 . 0 4 .85 at three locations . Average film thickness was determined by 30 . 5 59 . 6 9 . 9 6 . 25 subtracting the mean release liner /backing membrane thick 10 . 0 50 . 0 40 . 0 4 . 54 10 . 0 60 . 0 30 . 0 5 .27 ness from the mean patch thickness 15 . 1 49. 7 35 . 2 5 . 20 Drug in adhesive mixtures for adhesive Duro - Tak® 87 - 2677 required the addition of isopropyl alcohol ( 1 g Further solubility assessment was performed on a varietysty 20 before the addition of 4 g adhesive ) prior to casting to reduce of ternary and quaternary ( ternary mixture plus additive ) mixture viscosity and aid solvation . This additional solvent excipient mixtures, see Table 5 . The excipients selected for would be removed during drying . analyses were propylene glycol, Capryol 90® , Brij 93® , Table 6 below provides an example of an adhesive wet Brij 98® , Tween 80® and Cremphor EL® . The excipient casting mixture . mixtures were prepared , and their ropivacaine solubilities 25 were recorded , according to the protocols discussed above TABLE 6 for binary and ternary excipient mixtures. Wet casting mixture - 4 % ropivacaine in Duro - Tak ? 87 - 900A Target wt ( 4 g TABLE 5 30 adhesive % w / w % w / w Ropivacaine solubility ( % w / v ) in ternary and quaternary Component Common name batch ) ( g ) (wet basis ) (dry basis ) excipient mixtures prepared on a weight basis ropivacaine ropivacaine base 0 . 073 1 . 79 4 . 0 Duro - tak 87 - acrylate 4 .00 98 .21 96 . 0 % % % % % 900A * vinylacetate % capryol Brij Brij Tween Cremphor % 35 pressure Mixture PG 90 93 98 80 EL solubility sensitive adhesive 25 . 1 59 . 8 10 . 1 5 .0 4 . 53 *based on 43. 88 % solids ( % solids will vary between batches of adhesive ) 24 . 9 59 .8 10 . 2 5 . 1 4 . 70 25 . 0 59 . 8 10 . 2 . 5 . 0 4 .75 79. 9 13 . 3 6 . 8 4 . 21 Duro - Tak® 87 - 2677 and Duro - Tak® 87 - 900A demon 79 . 8 13 . 5 6 . 6 44: . 24 40 strated compatibility with release liner 3M 9741 ( fluoropo 80 .0 13. 3 6. 6 6 . 7 4 .28 lymer coated polypropylene film ) . Duro - Tak® 87 - 2074 8066. .0 7 11. 0 22 . 3 3 . 38 demonstrated compatibility with release liner 3M 1022 66 . 8 11 . 0 22 . 2 3 . 60 ( fluoropolymer coated polypropylene film ) . 66 . 7 11 . 0 22 . 3 3 . 77 A range of ropivacaine in adhesive patches prepared 45 according the above protocol are provided in Table 7 below : The solubility data presented in Tables 4 and 5 demon strates flexibility in the binary , ternary and quaternary mix TABLE 7 tures to be included in adhesives . Preparation of Transdermal Patches Ropivacaine ( API) in adhesive transdermal patch compositions Adhesive Only Patches 50 Example % API Adhesive Release liner Backing Patch formulations were typically prepared with 4 g of 87 -900A 9741 9730 (wet ) adhesive. 87 - 900A 9741 9730 Ropivacaine was weighed into a single vessel. Adhesive 5* 87 - 900A 9741 9730 was then added and vessel was capped . The vessel contents 5 87 - 2074 1022 9730 were mixed using a roller mixer until the mixture became 55 7 . 5 87 - 2074 1022 9730 10 87 - 2074 1022 9730 homogeneous and ropivacaine was fully dissolved . The 12 87 - 2074 1022 9730 adhesive mixture was then cast using a knife coater (Elcom 5 87 - 2677 9741 9730 eter ) at a suitable wet thickness onto a suitable release liner. 7 .5 87 - 2677 9741 9730 Except for those patches incorporating menthol, a wet film 10 10 * 87 - 2677 9741 9730 thickness was selected to produce a dry film thickness of 60 m 70 -95 um , or suitably 80 - 85 um . Typical casting thicknesses * drug precipitation observed hence patch above saturation were 450 um for Duro - Tak® 87 - 2677 , 350 um for Duro - Adhesive Plus One or More Excipients Tak® 87 - 900A and 520 um for Duro - Tak® 87 - 2074 adhe All formulations were prepared with 4 g of adhesive . The sive mixtures resulting in dry film thicknesses ranging loadings of other constituents (prepared as w / w ) , such as between 70 - 95 um . The wet film was dried at room tem - 65 excipients , were adjusted for percentage solids of adhesive , perature for 15 minutes , then at 50° C . for 5 minutes , and such that the patch loadings were relative to the dry adhesive finally at 90° C . for 10 minutes . The films were laminated weight. US 10 , 166 , 199 B2 18 Ropivacaine was weighed into a single vessel. The one or Further transdermal patch formulations containing adhe more excipients were added followed by the adhesive, and sive and a ternary mixture of excipients were prepared , as the vessel was capped . Isopropyl alcohol was added before shown in Table 9 below : the addition of the adhesive for preparations using Duro Tak® 87 - 2677 . The vessel contents were then mixed using 5 TABLE 9 a roller mixer until a homogeneous mixture was obtained , Ropivacaine (API ) in transdermal patches containing and the ropivacaine was fully dissolved . Casting thicknesses adhesive and a ternary mixture of excipients were adjusted to account for the inclusion of the excipient % [30 /60 / 10 ] mixture where appropriate . The mixtures were cast, dried % (PG / Capryol Release and laminated according to the protocols described for Example API Adhesive 90 /Brij 93 ) liner Backing adhesive only formulations . A transdermal patch containing 7 . 5 % ( w / w ) ropivacaine 15 4 87 - 900A 15 3M 9741 3M 9730 16 7 . 5 87 .- 262677 15 3M 9741 3M 9730 and 5 % ( w / w ) Transcutol® was successfully prepared 11 87 - 2074 15 3M 1022 3M 9730 according to the above protocol using Duro - Talc® adhesive 16 18 12 87 - 2074 15 3M 1022 3M 9730 87 - 2677 , 3M 9741 release liner and 3M 9730 occlusive backing membrane . Transdermal patches containing other ternary or quater Table 8 , below , provides a range of other transdermal nary mixtures of excipients were also prepared according to patches prepared according to the above protocol, each the above protocol, see Tables 10 and 11 below : containing a single excipient . 20 TABLE 10 TABLE 8 Ropivacaine (API ) in transdermal patches containing adhesive Ropivacaine (API ) in transdermal patches and a ternary or quaternary mixture of excipients containing adhesive and 1 excipient 25 Total Ex % Ex - Excip - excipient am - % Excip Release Backing am - % ient loading Release Backing API Excipient ient Adhesive liner membrane ple API mixture * ( % ) Adhesive liner membrane 11 4 Transcutol 5 87 - 900A 3M 9741 3M 9730 19 7 . 5 15 87 - 2677 3M 9741 3M 9730 P 30 20 7. 5 15 87 - 2677 3M 9741 3M 9730 4 Labrafac 87 - 900A 3M 9741 3M 9730 7. 5 15 87 - 2677 3M 9741 3M 9730 PG 7 . 5 iniinU 87 - 2677 3M 9741 3M 9730 Capryol 87 - 900A 3M 9741 3M 9730 23 7 . 5 87 - 2677 3M 9741 3M 9730 4 2 90 24 7 . 5 87 - 2677 3M 9741TI 3M 9730 Captex 5 87 - 900A 3M 9741 3M 9730 25 7 . 5 15 87 - 2677 3M 9741 3M 9730 355 35 BauWN * excipient mixture identified in Table 5 A binary excipient mixture containing propylene glycol and Brij® 93 demonstrated good compatibility with Duro TABLE 11 Tak® adhesive 87 -900A . A patch containing 10 % propylene Ropivacaine (API ) in transdermal patches containing adhesive glycol, 2 % ( w / w ) Brij® 93 and 4 % ropivacaine was pre - 40 and a ternary or quaternary mixture of excipients pared . Transdermal patches containing a ternary mixture of Ex am % Excipient Adhe - Release Thick excipients were prepared according to the above protocol. ple API component Backing Table 9 , below , provides an example of a wet casting sive liner (um ) mixture containing an adhesiveje and a ternaryternary excipient 4543 26 6 . 5 35 % 87 - 2677 3M 9741 3M 9730 - 92 [ 30 /60 /10 ] mixture : (PG /cap 90 /Brij93 ) TABLE 9 27 6 .5 35 % 87 - 2677 3M 9741 3M 9730 - 83 [30 /60 / 10 ] Wet casting mixture - 6 . 5 % ( w / w ) ropivacaine, 35 % ( w / w ) [ 30 /60 / 10 ] 50 (HG /cap propylene glycol/ Capryol ®90 /Brij ?93 in Duro - Tak ® 87 - 2677 90 /Brij93 ) 6 . 5 5 % 87 - 2677 3M 9741 3M 9730 ~ 84 Target Transcutol, wt ( 4 g 20 % adhesive % w / w % w / w [30 /60 /10 ] Component Common name (PG / cap batch ) g ) (wet basis ) (dry basis ) 55 90 /Brij93 ) ropivacaine ropivacaine base 0 . 1729 2 . 84 6 . 5 propylene 1 , 2 propandiol 0 . 2777 4 . 55 10 . 5 glycol EVA Membrane Release Studies Capyrol 90 propylene glycol 0 .5554 9 . 11 21. 0 monocaprylate type II Release studies were performed for selected transdermal Brij 93 Polyoxyethylene ( 2 ) 0 . 0926 1 . 52 3 . 5 60 patches and saturated aqueous solutions. For transdermal oleyl ether 0. 0926 1. 52 35 . 60 patches , circular ( 10 mm diameter ) samples were punched IPA 2 - propanol 1 . 00 16 . 4 out and applied to 3M 9702 CoTran® membranes (9 % EVA ) Duro - tak 87 - acrylate - vinylacetate 144: . 00 00 65616 . 6 58558 . 5 mounted in horizontal Franz- type diffusion cells . Saturated 2677 * pressure sensitive aqueous solutions were prepared at 32° C . (mixing time adhesive 65 218 -24 hours) . To avoid donor phase depletion , excess * based on 38 .68 % solids ( % solids will vary between batches of adhesive ) ropivacaine was added to the saturated solution when applied ( 1 ml) to 3M 9702 CoTran® membranes ( 9 % EVA ) US 10 , 166 , 199 B2 19 20 and donor chambers were occluded . The receptor medium immersing the cells in a thermostatically controlled water used was Walpole ' s acetate buffer pH4. The cells were bath (at 37° C . : 0 .5° C . ) . The receptor medium was continu immersed in a thermostatically controlled water bath at 32° ally stirred with a magnetic follower. Permeation of ropiva C . : 0 .5° C . and the receptor phase was continually agitated caine through the skin membrane was measured at five with a magnetic follower. Permeation of ropivacaine and 5 time -points over 24 hours . Samples of the receptor phase lidocaine through the EVA membrane wasmeasured at eight were analysed for active by HPLC and the permeated intervals over 48 hours ( typically at 1 , 2 , 4 , 6 , 8 . 12 . 24 and amounts (ug / cm²) and the mid time- point flux ( rate of 48 hours from dosing) . Each sample was placed into a delivery , ug / cm - / h ) were calculated . Mean - standard error pre - labelled 200 ul glass vial ( gold grade, Chromacol® ) and (SE ) data are presented . a PTFE cap was applied . If analysis could not be performed 10 Separation was performed on a C18 , 4 um , 150x4 . 6 mm HPLC column . An isocratic method was used and the mobile immediately , samples were frozen at - 20° C . pending analy phase was 35 /65 ( v / v ) acetonitrile / H , O plus 10 mM sodium sis . The liquid removed in each sample was replaced with heptane sulfonate and 0 .1 % acetic acid . The flow rate was 1 fresh , temperature - equilibrated blank receptor medium . ml/min and the runtime 10 minutes per sample . A 20 ul full Samples of the receptor phase were analysed for ropivacaine 15 loop injection was used for all samples and the column oven by HPLC and the permeated amounts were calculated (ug temperature was 35º C . Discrete wavelengths were collected cm ) . Suitable calibration plots were constructed using standard at 224 nm (amand wavelength used for quantitation ) and 263 solutions prepared in Walpole ' s acetate buffer pH 4 . The five nm plus UV scan data 210 - 310 nm were collected for peak level calibrations ranged from 0 .1 to 50 ug/ ml ropivacaine or identification purposes. The retention time for ropivacaine lidocaine. The limit of quantitation (LOO ) was the area for 202 was ~ 7 . 0 minutes and ~ 4 .6 minutes for lidocaine . Where calibration level 1 ( 0 . 1 ug /ml ) and any result below the LOQ required , samples were diluted into the calibration range was classed as a zero result . A quality assurance (QA ) ( 0 . 1 - 50 ug /ml ) . sample (calibration level 4 , 10 ug /ml ) was included in each Adhesive Only Patches analytical run . FIG . 6 demonstrates the poor in vitro human skin perme Adhesive Only Patches 25 ation properties of a saturated ropivacaine solution versus FIG . 1 compares the permeation , over 48 hours, of those1 of a saturated lidocaine solution ( both solutions con ropivacaine from the transdermal patch formulation pro tained excess solid ) . vided in Table 7 , together with a ropivacaine saturated FIG . 7 compares the in vitro human skin permeation , over aqueous solution and a ropivacaine saturated citrate acetate 48 hours , of ropivacaine from a patch containing 7 . 5 % buffer solution at pH 5 , using a 9 % EVA ( 3M 9702 ) 30 ( w / w ) ropivacaine in Duro - Tak® 87 -2677 adhesive , with a membrane . simple ropivacaine - saturated solution ( plus excess solid ) . Adhesive Plus One or More Excipients The effect of removing the patch after 24 hours is clearly FIG . 2 suggests that the permeation rate of ropivacaine shown (release of approximately 4 ug / cm² from the skin from a 4 % ( w / w ) ropivacaine in Duro - Tak® 87 - 900A is over the subsequent 24 hours ). greater than that from a 7 . 5 % ( w / w ) ropivacaine in Duro - 3 FIG . 8 demonstrates the in vitro human skin permeation , Tak® 87 - 2677 patch containing 5 % ( w / w ) Transcutol® . 35 over 24 hours , of ropivacaine from a patch containing 4 % FIG . 3 compares the permeation , over 48 hours , of ( w / w ) ropivacaine in Duro - Tak® 87 - 900A adhesive . Com ropivacaine from a simple ropivacaine - in -adhesive (Duro parison of this data with that of a 7 . 5 % ( w / w ) ropivacaine in Tak® 87 - 2677 ) patch , with one containing 15 % ( w / w ) of a Duro - Tak® 87 - 2677 adhesive showed similar in vitro ternary propylene glycol, Capryol® 90, Brij® 93 (30 /60 / 10 ) human skin permeation characteristics for both patches. excipient mixture . Improved permeation is observed for the 40 FIG . 9 demonstrates the mid time- point flux (ug / cm² h - ?) patch containing the ternary excipient mixture . for a 4 % ( w / w ) ropivacaine in Duro - Tak® 87 - 900A trans FIG . 4 compares the permeation , over 48 hours, of dermal patch . ropivacaine from selected transdermal patch formulations Adhesive Plus One or More Excipients provided in Table 10 , containing 15 % ( w / w ) of ternary / Table 12 , below , provides the in vitro human skin per quaternary excipient mixtures . All tested patches demon - 45 meation" values , over 24 hours , of ropivacaine from a patch strated similar permeation characteristics . containing 7 .5 % (w / w ) ropivacaine in Duro - Talc® 87 - 2677 FIG . 5 compares the permeation , over 48 hours , of adhesive, with an identical patch containing 15 % (w /w ) of ropivacaine from selected transdermal patch formulations a ternary propylene glycol, Capryol® 90, Brij® 93 ( 30 /60 / provided in Table 11 , with a transdermal patch containing an 10 ) excipient mixture . Permeation values for a 4 % ( w /w ) increased quantity of ropivacaine. The results demonstrate 50 ropivacaine in Duro - Tak® 87 - 900A adhesive are also pro that for patches having an increased quantity of excipient vided . mixture , improved permeation can be achieved using reduced quantities of dissolved ropivacaine . TABLE 12 In Vitro Human Skin Permeation Studies Ropivacaine in vitro human skin permeation from In vitro human skin permeation studies were performed adhesive only and ternary excipient mixture patches for selected transdermal patches and saturated aqueous solutions . For patches , circular ( 10 mm diameter ) samples ug / cm² (mean I SE ) were punched out and applied to human epidermal mem 7 . 5 % ropiv , branes (surgical excess abdominal tissue from 3 donors , Time 15 % [30 /60 / 10 ] n = 6 ) mounted in horizontal Franz - type diffusion cells . Satu 60 point ( PG / Cap 90 / Brij 93) in 7 . 5 % ropivacaine in 4 % ropivacaine in rated aqueous solutions were prepared at 32° C . (mixing 60 ( h ) 2677 (Example 16 ) 2677 ( Example 9 ) 900A (Example 2 ) time 218 - 24 hours ) . To avoid donor phase depletion , excess ropivacaine or lidocaine was added to the saturated solution 3 2 .65 + 0 .43 3 .92 + 1 .22 6 12 . 1 + 1 . 9 9 . 74 + 1 . 29 14 . 0 + 3 . 1 when applied ( 1 ml) to skin in vitro . Donor chambers were 9 23 . 1 + 3 . 1 23 . 7 + 4 . 3 occluded . The receptor medium was 25 /75 ( v /v ) ethanol/ pH 12 34 . 1 + 4 . 0 27 . 2 + 2 . 2 32 . 7 5 . 1 7 . 4 phosphate buffered saline ( EPBS ) and provided sink 65 24 75 .5 + 6 . 7 59 . 8 + 2 . 8 63 . 6 + 7 . 9 conditions for the test permeants ( < 10 % saturated ). Skin surface temperature was maintained at 32° C . - 1° C . by US 10 , 166 , 199 B2 21 22 Referring to Table 12 , FIG . 10 compares the in vitro Flux values for ropivacaine and lidocaine saturated aqueous human skin permeation , over 24 hours, of ropivacaine from solutions are also provided . Flux values were calculated a patch containing 7 .5 % (w / w ) ropivacaine in Duro - Talc® using a linear fit of the permeation data (as presented in 87 -2677 adhesive, with an identical patch containing 15 % FIGS . 7 , 8 , 10 and 12 ) during apparent steady - state delivery ( w /w ) of a ternary propylene glycol, Capryol® 90 , Brij® 93 5 and correlation coefficients are provided (r ? 20 . 998 through ( 30 /60 / 10 ) excipient mixture . Improved in vitro human skin out) . TABLE 14 In vitro human skin apparent steady - state flux values from ropivacaine transdermal patches, and ropivacaine and lignocaine saturated aqueous solutions Time Calculated flux Correlation Run range (h ) (ug . cm - . h - 1) coefficient , r 7 . 5 % Ropivacaine in 87 - 2677 ( Example 9 ) 4 -12 2 . 87 1 .000 Ropivacaine saturated H2O 4 - 12 2 . 52 1 .000 Lidocaine saturated H2O 4 - 12 70 . 7 0 . 999 4 % ropivacaine in 87 - 900A Example 2 ) 3 - 12 3 . 20 0 . 999 7 . 5 % Ropivacaine , 15 % [30 /60 / 10 ] (PG /Cap 3 - 12 3 .51 0 . 999 90 / Brij 93 ) in 87 - 2677 ( Example 16 ) 6 . 5 % Ropivacaine , 35 % [ 30 /60 / 10 ] (PG / Cap 3 - 12 4 . 19 0 .998 90 / Brij 93 ) in 87 - 2677 ( Example 26 ) 6 . 5 % Ropivacaine , 5 % menthol, 20 % [30 /60 / 10 ] 3 -12 3 .09 1 .000 (PG /Cap 90 /Brij 93 ) in 87- 2677 (Example 29 ) permeation is observed for the patch containing the ternary What is claimed is : excipient mixture . 1 . A transdermal patch comprising a pharmaceutical for Referring to Table 12 . FIG . 11 demonstrates the mid mulation , said formulation comprising : time- point flux (ug / cm² h - ) for a transdermal patch con - (i ) ropivacaine , taining 7. 5 % ( w / w ) ropivacaine and 15 % ( w / w ) of a ternary ( ii ) a pharmaceutically - acceptable adhesive, and propylene glycol, Capryol® 90 , Brij® 93 ( 30 /60 / 10 ) excipi- 30 ( iii ) two or three excipients selected from a penetration ent mixture in Duro - Tak® 87 - 2677 adhesive . enhancer , a hydrophilic material , and a carrier oil Table 13 , below , provides the in vitro human skin per having a ropivacaine solubility of greater than or equal meation values , over 24 hours , of ropivacaine from patches to 1 . 5 % ( w / w ) ; containing ternary and quaternary excipient mixtures, with a wherein said ropivacaine is present in its free base form and commercially available lidocaine transdermal patch ( Versta - 35 wherein said patch further comprises a backing membrane . tis ) . 2 . A transdermal patch as claimed in claim 1 , wherein the pharmaceutical formulation has an in vitro human skin TABLE 13 permeation rate of the ropivacaine that is greater than 1 . 8 ug cm - 2 h - 1. In vitro human skin permeation from ropivacaine 40 3 . A transdermal patch as claimed in claim 1 , wherein the and lignocaine transdermal patches pharmaceutical formulation has an in vitro human skin ug/ cm² (mean I SE ) permeation rate of the ropivacaine that is between 1 . 8 ug cm -2h - 1 and 10 ug cm -2 h - 7. 6 . 5 % ropiv , 6 . 5 % ropiv, 5 % menthol, 5 % lidocaine , Time 35 % [ 30 /60 / 10 ] 20 % [30 /60 / 10 ] ( PG /Cap Versatis 4 . A transdermal patch as claimed in claim 1 , wherein the point (PG /Cap 90 /Brij 93) in 90 / Brij 93) in 2677 Comparative 45 amount of the ropivacaine is between 3 and 20 % w / w . ( h ) 2677 ( Example 26 ) ( Example 29 ) example 1 ) 5 . A transdermal patch as claimed in claim 1 , wherein the adhesive has a ropivacaine solubility greater than 2 .5 % w / w 3 6 .07 + 1 . 68 3 . 56 + 0 . 66 5 . 33 + 1 . 23 6 17 . 5 3 . 2 12 . 7 + 1 . 5 14 . 7 + 1 . at room temperature . 9 29 . 8 + 4 . 5 22 . 2 = 2 . 2 28. 2 + 2 . 4 6 . A transdermal patch as claimed in claim 1 , wherein the 12 43 . 8 + 5 . 1 31 . 3 + 2 . 9 45. 4 3. 8 50 amount of adhesive is between 58 and 97 % w / w . 24 91. 9 1 9 . 0 63 . 4 + 5 . 0 127 .6 + 6 . 9 7 . A transdermal patch as claimed in claim 1 , wherein the adhesive is selected from acrylate / polyacrylate materials , rubbers or silicones. Referring to Table 13 , FIG . 12 compares the in vitro 8 . A transdermal patch as claimed in claim 1 , wherein the human skin permeation , over 24 hours , of ropivacaine from 55 adhesive is an acrylate copolymer material or an acrylate certain transdermal patches containing ternary or quaternary vinylacetate material. excipient mixtures, with a commercially - available ligno 9 . A transdermal patch as claimed in claim 1 , further caine transdermal patch ( Verstatis ) . comprising a carrier oil in an amount of between 2 . 5 and Referring to Table 13 , FIG . 13 compares the mid time 35 % w / w . point flux ( ug /cm “ h ) for certain transdermal patches 60 10 . A transdermal patch as claimed in claim 9 , wherein the containing ternary or quaternary excipient mixtures , and a carrier oil has a water solubility of less than 0 . 1 % w / w and commercially - available lignocaine transdermal patch ( Ver a ropivacaine solubility in excess of 3 % w / w . statis ) . 11 . A transdermal patch as claimed in claim 9 , wherein the Table 14 , below , provides the in vitro human skin appar - carrier oil is selected from the group consisting of sorbitan ent steady state flux values for ropivacaine , over either 3 - 12 65 monooleate , sorbitan trioleate , triglycerides of carprylic / or 4 - 12 hours, from patches containing either drug in adhe - capric acid , propylene glycol dicaprylate /dicaprate , ethoxy sive alone or with ternary and quaternary excipientmixtures . diglycol , propylene glycol monocaprylate , glycerol US 10 , 166 , 199 B2 23 24 monooleate , lanolin , acetylated lanolin , polyethylene glycol 16 . A transdermal patch as claimed in claim 1 , comprising lanolin , glycerol monocaprylate /caprate , propylene glycol propylene glycol monocaprylate , propylene glycol and poly laurate , and / or mono - or diglycerides of capric acid . oxyethylene oleyl ether present as a ternary mixture in an 12 . A transdermal patch as claimed in claim 1 , further comprising a penetration enhancer in an amount of between 5 amount of between 10 and 40 % w / w . 1 . 4 and 15 % w / w . 17 . A transdermal patch as claimed in claim 16 , wherein 13 . A transdermal patch as claimed in claim 12 . wherein the ternary mixture further comprises an additive selected the penetration enhancer is selected from the group consist from the group consisting of non - ionic surfactants , hydro ing of sugar fatty acid esters and ethers , C3- C , fatty alcohol, philic surfactants , terpenes and membrane disruptors . azone , oleic ethers, terpenes and ethoxy ethanols . 18 . A transdermal patch as claimed in claim 1 , wherein the 14 . A transdermal patch as claimed in claim 1 , further formulation comprises a penetration enhancer , a hydrophilic comprising a hydrophilic material in an amount of between material and a carrier oil having a ropivacaine solubility of 1 . 5 and 20 % w /w . greater than or equal to 1 . 5 % ( w / w ) . 15 . A transdermal patch as claimed in claim 14 , wherein the hydrophilic material is selected from the group consist 19 . A transdermal patch as claimed in claim 18 wherein ing of propylene glycol, glycerol, polyethylene glycol, short 15 the quantity of ( 111 ) present in the formulation is from 10 % chain water soluble esters of citric acid , acetic acid , hex ( w / w ) to about 40 % ( w / w ) . ylene glycol and alcohols , including diols and polyols .