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    公开号:ES2819211T9
    申请号:ES14784423T
    申请日:2014-10-07
    公开日:2021-08-06
    发明作者:Chris Jones；Darren Green
    申请人:Buzzz Pharmaceuticals Ltd；
    IPC主号:
    专利说明:

    [0002] Novel formulation
    [0004] Field of the invention
    [0006] The present invention relates to a new formulation. More specifically, the present invention relates to a new anesthetic or analgesic formulation suitable for transdermal administration. Such formulations are appropriate for the topical treatment of neuropathic and / or nociceptive pain. The present invention also relates to processes for the preparation of the formulations defined herein, as well as to these formulations for use in the topical treatment of neuropathic and / or nociceptive pain.
    [0008] Background of the invention
    [0010] Nociceptive pain is pain generated by nociceptors that respond to stimuli by sending nerve signals to the spinal cord and brain. Such signs can be indicative of tissue irritation, impending injury, or actual injury, and are often characterized as direct pain and / or aches. Examples of conditions associated with nociceptive pain include bone fractures, burns, bumps, bruises, inflammation (from an infection or arthritic disorder), arthralgia, general myalgia, and more specific myalgia caused by symptoms generally categorized as amplified musculoskeletal pain syndrome (AMP). .
    [0012] Neuropathic pain is pain caused by damage or disease that affects the somatosensory system. Neuropathic pain is the result of injury or malfunction in the central or peripheral nervous system. Pain is usually caused by an injury, but the injury does not need to involve actual damage to the central nervous system. Nerves can be infiltrated or compressed by tumors, strangulated by scar tissue, or inflamed by infection. Pain is usually characterized by burning, lancinating, cold, or so-called prick-type sensations. Persistent allodynia, pain resulting from a non-painful stimulus, such as a light touch, is also a common feature of neuropathic pain. The pain itself can have continuous and / or episodic (paroxysmal) components, with qualities similar to those of an electric shock. The pain can persist for months or years beyond the apparent healing of any damaged tissue. In these scenarios, such pain signals no longer represent an alarm about an ongoing or impending injury, but rather the alarm system itself that is failing. Common causes of painful peripheral neuropathies are herpes zoster, infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignant neoplasms, immune-mediated disorders, and physical trauma to a nerve stem. Neuropathic pain is also common in cancer, either as a direct result of cancer in the peripheral nerves (for example, through compression by a tumor) or as a side effect of chemotherapy radiation, injury or a surgery.
    [0014] Under certain conditions, pain can be caused by a complex mix of nociceptive and neuropathic factors. For example, myofascial pain is understood to be the result of nociceptive input from muscles. However, it is plausible that such abnormal muscle activity is itself the result of neuropathic conditions.
    [0016] In both neuropathic and nociceptive types of disease, neurons become unusually sensitive and develop spontaneous activity, abnormal excitability, and increased sensitivity to chemical, thermal, and mechanical stimuli. This phenomenon is known as "peripheral sensitization". Localized administration of anesthetic can provide a method to desensitize aberrant stimuli.
    [0018] Lidocaine (often referred to as lignocaine) is widely used as a local anesthetic and is commercially available in both injectable and transdermal patch forms. When compared to a systemic dose, transdermal administration of local anesthetics provides prolonged anesthesia at the target site for pain suppression and involves reduced plasma levels, hence reduced potential toxicity.
    [0019] However, despite the widespread use of lignocaine transdermal patches, there remains a need for better transdermal anesthetic formulations.
    [0021] Furthermore, there remains a need for improved analgesic transdermal patch formulations to provide analgesia, in particular improved patches for the administration of opioid analgesics.
    [0023] There is also a need for transdermal formulations that have good skin permeation properties. Furthermore, there is a need for transdermal formulations of anesthetic or analgesic agents that exhibit improved pharmacological potency and that have a longer duration of action to reduce the occurrence of episodic pain.
    [0025] Aspects of the invention were devised with the foregoing in mind.
    [0027] EP 2759294 A1 relates to a transdermal preparation comprising sequentially stacked layers of a support layer, a barrier layer, a drug adhesive layer and a layer of release, wherein the drug adhesive layer comprises a drug selected from fentanyl and an analog and a pharmaceutically acceptable salt thereof, a skin penetration enhancer, and a polyacrylate adhesive selected from a non-functional polyacrylate adhesive and a polyacrylate adhesive containing carboxyl. US 2002/197284 refers to the transdermal administration of local anesthetic agents. Summary of the invention
    [0028] The present invention provides a transdermal patch comprising a pharmaceutical formulation, said formulation comprising:
    [0029] (i) ropivacaine;
    [0030] (ii) a pharmaceutically acceptable adhesive;
    [0031] and additionally a penetration enhancer selected from fatty acid esters and ethers of sugar, C8-C18 fatty alcohol, azone, oleic ethers, terpenes and ethoxyethanols;
    [0032] and additionally a hydrophilic material;
    [0033] and additionally a carrier oil selected from sorbitan monooleate, sorbitan trioleate, carboxy / capric acid triglycerides, propylene glycol dicaprylate / dicaprate, ethoxy diglycol, propylene glycol monocaprylate, glycerol monooleate, lanolin, acetylated lanolin, polyethylene glycol monooleate, lanolin glycerol caprate, propylene glycol laurate and / or capric acid mono or diglycerides;
    [0034] wherein the patch further comprises a support membrane.
    [0035] The invention also provides a pharmaceutical formulation suitable for inclusion in a transdermal patch according to the invention, wherein said formulation is as defined in the claims.
    [0036] The invention also provides a pharmaceutical formulation of the invention or a transdermal patch of the invention for use as a medicament.
    [0037] The invention also provides a pharmaceutical formulation of the invention or a transdermal patch of the invention for use in the treatment of pain or in the treatment of one or more of the neuropathic and nociceptive pain.
    [0038] The invention also provides a method of preparing a pharmaceutical formulation of the invention, said method comprising mixing:
    [0039] (i) ropivacaine;
    [0040] (ii) an adhesive as set forth in the claims; and
    [0041] (iii) three excipients selected from a penetration enhancer as set out in the claims, a hydrophilic material as set out in the claims and a carrier oil as set out in the claims.
    [0042] Additional aspects of the invention are set forth in the claims.
    [0043] Disclosure Summary
    [0044] The present disclosure describes a new pharmaceutical formulation suitable for topical application for the treatment of pain, for example, nociceptive and / or neuropathic pain.
    [0045] Thus, herein is described a transdermal patch comprising a pharmaceutical formulation, said formulation comprising ropivacaine or an opioid and a pharmaceutically acceptable adhesive, and wherein said formulation has an in vitro permeation rate greater than 1.8 | ig cm -2 h-1.
    [0046] Also described is a transdermal patch comprising a pharmaceutical formulation, said formulation comprising:
    [0047] (i) ropivacaine or an opioid,
    [0048] (ii) a pharmaceutically acceptable adhesive and optionally
    [0049] (iii) one or more than a penetration enhancer, a hydrophilic material, and a carrier oil having a ropivacaine or opioid solubility greater than or equal to 1.5% (w / w).
    [0050] Also described is a pharmaceutical formulation suitable for inclusion in a transdermal patch as defined herein, said formulation comprising ropivacaine or an opioid and an adhesive. pharmaceutically acceptable, and in which said formulation has an in vitro human skin permeation rate greater than 1.8 | ig cm-2 h-1.
    [0052] A pharmaceutical formulation comprising:
    [0054] (i) ropivacaine or an opioid,
    [0056] (ii) a pharmaceutically acceptable adhesive and optionally
    [0058] (iii) one or more of any one a penetration enhancer, a hydrophilic material, and a carrier oil having a ropivacaine or opioid solubility greater than or equal to 1.5% (w / w).
    [0060] wherein said formulation is suitable for inclusion in a transdermal patch as defined herein.
    [0062] Also described is a pharmaceutical formulation or transdermal patch as defined herein for use as a medicament.
    [0064] Also described is a pharmaceutical formulation or transdermal patch as defined herein for use in the treatment of pain (eg, neuropathic and / or nociceptive pain).
    [0066] Also described is a method of treating pain (eg, neuropathic and / or nociceptive pain), said method comprising topically administering to a human or animal subject in need of such treatment a therapeutically effective amount of a pharmaceutical formulation as defined in this document, or apply a transdermal patch as defined herein.
    [0068] Also described is a method of preparing a pharmaceutical formulation as defined herein, said method comprising mixing:
    [0070] (i) ropivacaine or an opioid,
    [0072] (ii) an adhesive as defined herein, and optionally
    [0074] (iii) one or more than a penetration enhancer as defined herein, a hydrophilic material as defined herein, and a carrier oil as defined herein and having a ropivacaine or opioid solubility greater than or equal to 1.5% (p / p).
    [0076] Detailed description
    [0078] Ropivacaine
    [0080] Ropivacaine, chemical name (2S) -N- (2,6-dimethylphenyl) -1-propyl-2-piperidinecarboxamide and having the structure shown below, is an aminoamide that contains an asymmetric carbon atom and is produced as the only S enantiomer for clinical use as a local anesthetic.
    [0085] Studies focusing on the use of local anesthetics during cataract surgery have shown that, dose for dose, ropivacaine can be up to four times more potent than lidocaine anesthetics. In this study, the use of ropivacaine was preferred over lidocaine due to its longer half-life, which contributed to a reduction in levels of episodic pain.
    [0087] In view of the above advantages, ropivacaine presents an appropriate candidate for inclusion in a transdermal patch for the treatment of pain, such as nociceptive and neuropathic pain. In theory, such advantages would allow for a transdermal patch having improved drug potency and improved drug persistence characteristics.
    [0088] However, despite the advantages discussed above, it has been shown that e1H2O saturated with ropivacaine exhibits significantly worse skin permeation characteristics than e1H2O saturated with lidocaine (see Figure 6), thus presenting a considerable barrier to patch development. transdermal.
    [0090] When used in conjunction with the present disclosure, ropivacaine can be present in its free base form or as a salt. Appropriately, when used as part of the pharmaceutical formulation described herein, ropivacaine is present in its free base form, as it is commonly understood that the skin is generally more permeable to uncharged lipophilic permeants, as opposed to charged species. The free base form would also be expected to be more soluble in typical pharmaceutical adhesives than a salt form (eg, ropivacaine HCl).
    [0092] The amount of ropivacaine present in the pharmaceutical formulation of the present disclosure will depend on how soluble it is in the present pharmaceutically acceptable adhesive and excipients. Generally, ropivacaine will be present in an amount of 3 to 20% w / w.
    [0094] In one case, the amount of ropivacaine is between 3 and 10% w / w.
    [0096] Suitably, the amount of ropivacaine is between 6 and 8% w / w.
    [0098] Opioid pain relievers
    [0100] The transdermal patches of the present disclosure may comprise an opioid analgesic. Any appropriate opioid pain reliever can be used.
    [0102] In one case, the opioid pain reliever is selected from morphine, codeine, thebaine, diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine, acetylpropionylzoyldomorphine, hydrocodone morphine, dibenorphine, hydrocodonehydromine , oxycodone, oxymorphone, ethylmorphine and buprenorphine, fentanyl, pethidine, levorphanol, methadone, tramadol, and dextropropoxyphene.
    [0104] In another case, the opioid pain reliever is oxycodone.
    [0106] The amount of opioid present in the pharmaceutical formulation of the present disclosure will depend on how soluble it is in the present pharmaceutically acceptable adhesive and excipients. Typically, the opioid will be present in an amount of 3 - 20% w / w.
    [0108] In one case, the amount of opioid is between 3 and 10% w / w.
    [0110] Appropriately, the amount of opioid is between 6 and 8% w / w.
    [0112] Transdermal patch
    [0114] Despite the poor in vitro skin permeation observed with a saturated ropivacaine solution compared to a saturated lidocaine solution (see Figure 6), it has surprisingly been found that it is possible to prepare a transdermal ropivacaine delivery system.
    [0116] The transdermal patches of the present disclosure are prepared by molding a layer of wet pharmaceutical formulation as described herein with a known thickness over an appropriate release coating. In its simplest form, the pharmaceutical formulation may comprise ropivacaine or an opioid and a pharmaceutically acceptable adhesive. The pharmaceutical formulation may further comprise one or more additional excipients, including a carrier oil, penetration enhancers, and hydrophilic materials. Generally, the pharmaceutical formulation is molded to a wet thickness of between about 240 µm and about 550 µm, to provide a dry thickness of between about 45 µm and about 95 µm, suitably between about 80 µm. | im and approximately 85 | im. After molding, the layer is dried and then laminated with a support membrane. An appropriate container or closure system can be used to protect the transdermal patch during transport and storage.
    [0118] Appropriate support membranes can be occlusive or non-occlusive. When using a non-occlusive backing membrane, it is desirable to use a fully occlusive container or closure system to avoid degradation of the molded pharmaceutical formulation layer prior to use. The support membrane can be of any thickness, but suitably has a thickness of between about 10 and 260 µm. Suitable materials include, but are not limited to, synthetic polymers including, for example, polyesters, polycarbonates, polyimides, polyethylene, polyethylene terephthalate, polypropylene, polyurethanes, and polyvinyl chlorides. The supporting membrane can also be a laminate comprising additional layers that can include vapor-deposited metal, such as aluminum, additional synthetic polymers, and other materials, to allow heat sealing, such as EVA copolymer. Suitably, the support membrane comprises occlusive Scotchpak 9730® available from 3M.
    [0119] The release liner is generally placed on an opposite surface of the pharmaceutical formulation layer to the support membrane and provides a removable waterproof or protective layer, usually but not necessarily rendered non-stick so as not to adhere to the pharmaceutical formulation layer. The release liner serves to protect the pharmaceutical formulation layer during storage and transit, and is intended to be removed during use. The release liner can be formed from the same materials used for the support membrane, but can be formed from metallic foils, Mylar®, polyethylene terephthalate, silicone polyester, fumed silica on silicone rubber, polytetrafluoroethylene, cellophane , silicone paper, aluminized paper, polyvinyl chloride film, composite sheets or films containing polyester such as polyester terephthalate, aluminized polyester or polyester, polytetrafluoroethylene, polyether block amide copolymers, polyethylene methyl methacrylate block copolymers , polyurethanes, polyvinylidene chloride, nylon, silicone elastomers, rubber-based polyisobutylene, styrene, styrene-butadiene, and styrene-isoprene, polyethylene, and polypropylene copolymers.
    [0121] Suitably, the release liner is an occlusive or semi-occlusive backing film that is compatible with the pharmaceutically acceptable adhesive present in the pharmaceutical formulation layer.
    [0123] Appropriately, the release liner can be selected from Scotchpak 9741®, Scotchpak 1022®, Scotchpak 9742®, Scotchpak 9744®, Scotchpak 9748®, and Scotchpak 9755®, all of which are available from 3M and comprise fluoropolymers coated on polypropylene. or polyester film. Other appropriate release liners manufactured by other manufacturers can also be used. The release liner can be of any thickness known in the art. Suitably, the release liner is about 0.01mm to about 2mm thick.
    [0125] In one case, the release liner is Scotchpak 9741®. In another case, the release liner is Scotchpak 1022®.
    [0127] The container or closure system can be made of a variety of appropriate materials to protect the packaged transdermal patch from moisture and light.
    [0129] Ropivacaine or opioid permeation rate
    [0131] As indicated above, the present disclosure provides a transdermal patch comprising a pharmaceutical formulation, said formulation comprising ropivacaine or an opioid and a pharmaceutically acceptable adhesive, and wherein said formulation has a permeation rate of ropivacaine or opioid in human skin. in vitro that is greater than 1.8 | ig cirr2 h-1. Ropivacaine or opioid permeation through human skin has been measured from selected patches and saturated solutions. Measurements of ropivacaine or opioid permeation / release through a 9% EVA membrane were used as a tool to select candidate patches. Permeation / release data were only recorded for those patches that remained free of ropivacaine or opioid precipitation (that is, those that were below saturation concentration).
    [0133] The present disclosure also provides a pharmaceutical formulation, said formulation comprising ropivacaine or opioid and a pharmaceutically acceptable adhesive, and wherein said formulation has a ropivacaine or opioid permeation rate in human skin in vitro greater than 1.8 | ig cirr2 h- 1.
    [0135] By in vitro human skin permeation rate is meant the rate of delivery of ropivacaine or opioid through human epidermal membranes over time periods of up to 12 hours.
    [0137] Appropriately, the in vitro human skin permeation rate of ropivacaine or opioid is the apparent steady-state flux (calculated from the roughly linear portion of the cumulative permeation profile), typically observed between 3 and 12 hours. , or between 4 and 12 hours, when evaluated under the conditions detailed in the following sections.
    [0139] In one case, the in vitro human skin permeation rate of ropivacaine or opioid is between 1.8 | ig cirr2 h-1 and 10 | ig cirr2 h-1.
    [0141] In another case, the in vitro human skin permeation rate of ropivacaine or opioid is between 2 | ig cirr2 Ir1 and 6 | ig cirr2 h-1.
    [0143] In another case, the in vitro human skin permeation rate of ropivacaine or opioid is between 3 | ig cm-2 h-1 and 5 | ig cm-2 h-1.
    [0145] Pharmaceutically acceptable adhesive
    [0147] The pharmaceutically acceptable adhesive is selected both in terms of its ability to solubilize ropivacaine or an opioid, and its tack and peel adhesive properties.
    [0149] In one case, the adhesive has a solubility in ropivacaine or opioid greater than 2.5% w / p at room temperature.
    [0150] Any suitable adhesive can be used. In one case, the adhesive is selected from acrylate / polyacrylate materials, rubbers, and silicones. Suitably, the adhesive is an acrylate or polyacrylate material, including acrylate and acrylate-vinyl acetate copolymers, such as Duro-Tak 87-2677®, Duro-Tak 87-900A®, Duro-Tak 87-2074 ®, Duro-Tak 87-2054®, Duro-Tak 87-2052®, Duro-Tak 87-2196®, available from Henkel. In another case, the adhesive is selected from Duro-Tak 87-900A®, Duro-Tak 87-2677® and Duro-Tak 87-2074®, which has approximately 4% (w / w), 8% (w / w ) and 12% (w / w) of ropivacaine solubility respectively and exhibiting excellent peeling and stickiness behavior.
    [0151] Suitably the adhesive is Duro-Tak 87-2677®.
    [0152] In one case, an appropriate volatile solvent is added to the adhesive to reduce viscosity and aid solvation. Appropriate solvents may include, but are not limited to, isopropyl alcohol, methanol, ethanol, and ethyl acetate. Generally, the amount of adhesive is between 58 and 97% w / w.
    [0153] Carrier oil
    [0154] The carrier oil is selected both for its compatibility with the pharmaceutically acceptable adhesive and for its ability to solubilize the ropivacaine or opioid. Carrier oils used in conjunction with the present disclosure include, but are not limited to, sorbitan monooleate, sorbitan trioleate, carboxy / capric acid triglycerides, propylene glycol dicaprylate / dicaprate, ethoxy diglycol, propylene glycol monocaprylate, glycerol lan monooleate. , acetylated lanolin, polyethylene glycol lanolin, glycerol monocaprylate / caprate, propylene glycol laurate and / or capric acid mono- or diglycerides.
    [0155] Suitably, the carrier oil has a water solubility of less than 0.1% (w / w) and a ropivacaine or opioid solubility of greater than 3% (w / w).
    [0156] Suitably the carrier oil may be sorbitan trioleate, propylene glycol monocaprylate, glycerol monocaprylate / caprate, propylene glycol laurate and / or capric acid mono or diglycerides. Suitably, the carrier oil is present in the pharmaceutical formulation at a concentration of between about 2.5% (w / w) and about 35% (w / w).
    [0157] In one case, the carrier oil is in an amount between 9 and 21% w / w.
    [0158] Suitably, the carrier oil is in an amount between 12 and 21% w / w.
    [0159] Suitably, the carrier oil has a ropivacaine or opioid solubility greater than 4% (w / w).
    [0160] Suitably, the carrier oil may be propylene glycol monocaprylate, propylene glycol laurate and / or capric acid mono- or diglycerides. Even more appropriately, the carrier oil is propylene glycol monocaprylate, which is available under the trade name Capryol 90®.
    [0161] In one case, the carrier oil is included in the pharmaceutical formulation without any other excipients.
    [0162] Suitably, the carrier oil is included in the pharmaceutical formulation as part of a ternary mixture that includes both a penetration enhancer and a hydrophilic material.
    [0163] In another case, the carrier oil is included in the pharmaceutical formulation as part of a quaternary mixture that includes a penetration enhancer, a hydrophilic material, and an additive selected from nonionic surfactants, hydrophilic surfactants, terpenes, and double membrane disruptors, including those obtainable under the trade names Transcutol®, Brij 98®, Tween 80®, Cremphor EL® and menthol.
    [0164] Penetration enhancer
    [0165] The penetration enhancers used in conjunction with the present disclosure serve to promote percutaneous absorption of ropivacaine or opioid by temporarily decreasing the impermeability of the skin. Importantly, when included in the pharmaceutical formulations of the present disclosure, the penetration enhancer should not compromise the release characteristics of the adhesive.
    [0166] Appropriately, the penetration enhancer and the amounts in which it is added should be non-toxic, non-irritating, non-allergenic, odorless, tasteless, colorless, soluble, and compatible with ropivacaine or the opioid and the other excipients described herein. document. Importantly, the enhancer should not cause the loss of body fluids, electrolytes, and other endogenous materials, and the skin should immediately regain its barrier properties upon removal. Examples of appropriate penetration enhancers for inclusion in the pharmaceutical formulation of the present disclosure include, but are not limited to, fatty acid esters and ethers of sugar, Cs-C-is fatty alcohol, azone, oleic ethers, terpenes and ethoxyethanols. Appropriately, when used, the penetration enhancer is present in the pharmaceutical formulation at a concentration of between about 1.4% (w / w) and about 15% (w / w).
    [0167] Suitably, the penetration enhancer is in an amount between 1.5 and 4 % w / w.
    [0168] Suitably, the penetration enhancer can be polyoxyethylene oleyl ether, available under the trade name Brij 93®, or 2- (2-ethoxyethoxy) ethanol, available under the trade name Transcutol®, or menthol.
    [0169] In one case, the penetration enhancer is included in the pharmaceutical formulation without any other excipients. In another case, the penetration enhancer is included in the pharmaceutical formulation as part of a binary mixture that includes a carrier oil or a hydrophilic material.
    [0170] Suitably, the penetration enhancer is included in the pharmaceutical formulation as part of a ternary mixture that includes both a carrier oil and a hydrophilic material.
    [0171] In another case, the penetration enhancer is included in the pharmaceutical formulation as part of a quaternary mixture that includes a carrier oil, a hydrophilic material, and an additive selected from nonionic surfactants, hydrophilic surfactants, terpenes (such as menthol), and disruptors. membrane, including those available under the trade names Transcutol®, Brij 98®, Tween 80®, and Cremphor EL®.
    [0172] Hydrophilic material
    [0173] The hydrophilic materials used in conjunction with the present disclosure can aid skin absorption of the ropivacaine or the opioid. The hydrophilic material can be present as a polar enhancer, and is liquid at skin temperature. Appropriately, the hydrophilic material and the amounts in which it is added should be non-toxic, non-irritating, non-allergenic, odorless, tasteless, colorless, soluble, and compatible with ropivacaine or opioid and the other excipients described herein.
    [0174] In one instance, the hydrophilic material will have a hydrophilic-lipophilic balance (HLB) greater than 7. Examples of suitable hydrophilic materials for inclusion in the pharmaceutical formulation of the present disclosure include, but are not limited to, propylene glycol, glycerol, polyethylene glycol short chain, water soluble citric acid esters, acetic acid, hexylene glycol, and alcohols, including diols and polyols. Appropriately, when used, the hydrophilic material is present in the pharmaceutical formulation at a concentration of between about 1.5% (w / w) and about 20% (w / w).
    [0175] Suitably, the hydrophilic material is in an amount between 6 and 11% w / w.
    [0176] Suitably the hydrophilic material is propylene glycol.
    [0177] In one case, the hydrophilic material is included in the pharmaceutical formulation as part of a binary mixture that includes either a carrier oil or a penetration enhancer.
    [0178] Suitably, the hydrophilic material is included in the pharmaceutical formulation as part of a ternary mixture that includes both a carrier oil and a penetration enhancer.
    [0179] Otherwise, the hydrophilic material is included in the pharmaceutical formulation as part of a quaternary mixture that includes a carrier oil, a penetration enhancer, and an additive selected from nonionic surfactants, hydrophilic surfactants, terpenes (such as menthol), and disruptors. membrane, including those materials obtainable under the trade names Transcutol®, Brij 98®, Tween 80® and Cremphor EL®.
    [0180] Excipient combinations
    [0181] As indicated in the preceding paragraphs, the pharmaceutical formulations of the present disclosure optionally comprise one or more excipients in addition to the ropivacaine or opioid and the pharmaceutically acceptable adhesive. Suitably, the pharmaceutical formulation comprises two excipients present as a binary mixture and, more appropriately, the pharmaceutical formulation comprises three excipients present as a ternary mixture. It has been shown that for pharmaceutical formulations containing ternary mixtures of excipients, enhanced transdermal release of ropivacaine or an opioid can be achieved.
    [0182] Binary or ternary mixtures can enhance transdermal release of ropivacaine or opioid by temporarily altering skin barrier function, or by improving drug / skin partition resulting from increased solubility of the drug in the stratum corneum. The selection of binary / ternary / quaternary mixtures is designed to maintain reasonable solubility of the ropivacaine or opioid in the pharmaceutically acceptable adhesive. The binary / ternary / quaternary mixture need not increase the solubility of the drug in the pharmaceutically acceptable adhesive. In certain cases, the solubility of ropivacaine or opioid in selected ternary mixtures of excipients is greater than the solubility of ropivacaine or opioid in each individual excipient. In such cases, the observed solubility is significantly greater than the predicted solubility based on Proportional contributions of solubilities in individual excipients, suggesting a significant cooperative effect on drug solubility.
    [0184] The inclusion of one or both of a penetration enhancer and / or a hydrophilic material in the binary or ternary mixtures can contribute to improve the transdermal administration of ropivacaine or opioids by increasing the permeation of the skin according to the mechanisms discussed in the previous paragraphs.
    [0186] Binary mixtures
    [0188] The binary mixtures for use in conjunction with the present disclosure contain two excipients selected from a carrier oil, a penetration enhancer, and / or a hydrophilic material.
    [0190] In one case, the amount of binary mixture present in pharmaceutical formulations is from about 5% (w / w) to about 40% (w / w). Appropriately, from about 10% (w / w) to about 35% (w / w).
    [0192] Optionally, the binary mixture may contain one or more additives, selected from the group consisting of nonionic surfactants, hydrophilic surfactants, terpenes (such as menthol), and membrane disruptors. Suitable additives include, but are not limited to, those obtainable under the trade names Transcutol®, Brij 98®, Tween 80®, and Cremphor EL®.
    [0194] In one case, the binary mixture comprises a penetration enhancer selected from the group consisting of polyoxyethylene oleyl ether, obtainable under the trade name Brij 93®, or 2- (2-ethoxyethoxy) ethanol, obtainable under the trade name Transcutol® and a hydrophilic material selected from the group consisting of propylene glycol, glycerol, polyethylene glycol, short chain water soluble esters of citric acid, acetic acid, hexylene glycol and alcohols, including diols and polyols.
    [0196] In another instance, the binary mixture comprises a carrier oil selected from the group consisting of propylene glycol monocaprylate, propylene glycol laurate, and / or capric acid mono or diglycerides, and a penetration enhancer selected from the group consisting of polyoxyethylene oleyl ether. , which can be obtained under the trade name Brij 93®, or 2- (2-ethoxyethoxy) ethanol, which can be obtained under the trade name Transcutol®.
    [0198] Suitably, the binary mixture comprises propylene glycol monocaprylate, available under the trade name Capryol 90®, and polyoxyethylene oleyl ether, available under the trade name Brij 93®.
    [0200] In another case, the binary mixture comprises a carrier oil selected from the group consisting of propylene glycol monocaprylate, propylene glycol laurate and / or capric acid mono or diglycerides, and a hydrophilic material selected from the group consisting of propylene glycol, glycerol, polyethylene glycol, Short chain water soluble esters of citric acid, acetic acid, hexylene glycol, and alcohols, including diols and polyols.
    [0202] Suitably, the binary mixture comprises propylene glycol monocaprylate, obtainable under the trade name Capryol 90®, and propylene glycol.
    [0204] Ternary mixtures
    [0206] Ternary mixtures for use in conjunction with the present disclosure contain a carrier oil, a penetration enhancer, and a hydrophilic material.
    [0208] In one case, the amount of ternary mixture present in pharmaceutical formulations is from about 10% (w / w) to about 40% (w / w), suitably from about 15% (w / w) to about 35%. (w / w), and more appropriately about 35% (w / w).
    [0210] Optionally, the ternary mixture may contain one or more additives, selected from the group consisting of nonionic surfactants, hydrophilic surfactants, terpenes (such as menthol), and membrane disruptors. Suitable additives include, but are not limited to, those obtainable under the trade names Transcutol®, Brij 98®, Tween 80®, and Cremphor EL®.
    [0212] In one instance, the ternary mixture comprises a carrier oil selected from the group consisting of propylene glycol monocaprylate, propylene glycol laurate and / or capric acid mono or diglycerides; a penetration enhancer selected from the group consisting of polyoxyethylene oleyl ether, available under the trade name Brij 93®, or 2- (2-ethoxyethoxy) ethanol, available under the trade name Transcutol®; and a hydrophilic material selected from the group consisting of propylene glycol, glycerol, polyethylene glycol, short chain water soluble esters of citric acid, acetic acid, hexylene glycol, and alcohols, including diols and polyols.
    [0214] Suitably, the ternary mixture comprises propylene glycol monocaprylate, obtainable under the trade name Capryol 90®; polyoxyethylene oleyl ether, available under the trade name Brij 93®; and propylene glycol.
    [0215] Preparation of pharmaceutical formulations.
    [0217] The pharmaceutical formulations of the present disclosure can be prepared using standard techniques known in the art.
    [0219] Pharmaceutical formulations are appropriately prepared by mixing all the components.
    [0221] Individual components can be mixed by simply adding all components at the same time in a mixing container and then mixing them all together (a "one-pot" mix). Alternatively, the components can be added sequentially in two or more steps or stages. Appropriately, when more than one excipient is part of the formulation, such excipients can be premixed to form binary or ternary excipient mixtures, which can be subsequently mixed with the other components of the formulation.
    [0223] Other experimental conditions required to prepare the formulations of the present disclosure, such as mixing times, mixing equipment, temperature control, etc., can be readily determined by one of ordinary skill in the art.
    [0225] Additional experimental details will also be apparent from the accompanying examples.
    [0227] Once prepared, the pharmaceutical formulations of the present disclosure are formed into a transdermal patch for topical application.
    [0229] Therapeutic uses
    [0231] The pharmaceutical formulations of the present disclosure are particularly suitable for the treatment of pain. Once administered, the transdermal patch comprising the pharmaceutical formulation provides a localized release of the ropivacaine or opioid, thereby providing pain relief at a desired location. During localized administration, amounts of ropivacaine or opioid can be absorbed into the patient's bloodstream, thus providing additional systemic administration of the anesthetic.
    [0233] The types of pain that can be treated with the transdermal patch of the present disclosure include nociceptive and neuropathic pain.
    [0235] Nociceptive pain can be pain associated with tissue irritation, impending injury, or actual injury and is often characterized by pain and / or direct aches and pains. Examples of conditions associated with nociceptive pain include bone fractures, burns, bumps, bruises, inflammation (from an infection or arthritic disorder), arthralgia, general myalgia, and more specific myalgia caused by symptoms generally categorized as amplified musculoskeletal pain syndrome (AMP). .
    [0237] Neuropathic pain is pain caused by damage or a disease that affects the somatosensory system. The pain is usually characterized by burning, lancinating, cold, or so-called prick-like sensations. Persistent allodynia, pain resulting from a non-painful stimulus, such as a light touch, is also a common feature of neuropathic pain. The pain itself can have continuous and / or episodic (paroxysmal) components, with qualities similar to those of an electric shock. Common causes of painful peripheral neuropathies that can be treated with the transdermal patches of the present disclosure include herpes zoster, infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignant neoplasms, immune-mediated disorders, and physical trauma to a trunk. highly strung. Neuropathic pain is also common in cancer, either as a direct result of cancer in the peripheral nerves (for example, through compression by a tumor) or as a side effect of chemotherapy radiation, injury or a surgery.
    [0239] The transdermal patches of the present disclosure may also be effective in cases where pain is caused by a complex mix of nociceptive and neuropathic factors, eg, myofascial pain.
    [0240] The pharmaceutical compositions of the present disclosure can be used alone as the sole therapy. Alternatively, the compositions can be administered as part of combination therapy with one or more other pain treatments or anesthetics. Such conjoint treatment can be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment.
    [0242] Detailed description of the drawings
    [0244] The present disclosure is further defined with reference to the accompanying figures, in which the data is presented as a mean ± standard error (SE), and where:
    [0246] Figure 1 compares the 48 hour permeation of ropivacaine from a variety of transdermal patches of the present disclosure, with a saturated aqueous solution of ropivacaine and a buffer solution of saturated ropivacaine citrate acetate at pH 5, using a continuous membrane. EVA (3M 9702).
    [0247] Figure 2 compares the 48 hour permeation of ropivacaine from a variety of transdermal patches of the present disclosure with a saturated aqueous solution of ropivacaine using a continuous EVA membrane (3M 9702).
    [0248] Figure 3 compares the permeation, during 48 hours, of ropivacaine of a simple patch of ropivacaine in adhesive (Duro-Tak® 87-2677), with one that contains 15% (w / w) of a mixture of ternary propylene glycol excipients, Capryol®90, Brij®93 (30/60/10), using continuous EVA membrane (3M 9702).
    [0249] Figure 4 compares the 48 hour permeation of ropivacaine of various transdermal patches of the present disclosure, using a continuous EVA membrane (3M 9702).
    [0250] Figure 5 compares the 48 hour permeation of ropivacaine of various transdermal patches of the present disclosure, using a continuous EVA membrane (3M 9702).
    [0251] Figure 6 compares the in vitro human skin permeation properties of a saturated solution of ropivacaine versus a saturated solution of lignocaine.
    [0252] Figure 7 compares the permeation of human skin in vitro, for 48 hours, of ropivacaine from a patch containing 7.5% (w / w) of ropivacaine in Duro-Tak® 87-2677 adhesive, with a saturated solution of plain ropivacaine. .
    [0253] Figure 8 demonstrates the in vitro permeation of human skin, for 48 hours, of ropivacaine from a patch containing 4% (w / w) ropivacaine in Duro-Tak® 87-900A adhesive.
    [0254] Figure 9 demonstrates the midpoint flow time) of ropivacaine to a 4% (w / w) ropivacaine in the Duro-Tak® 87-900A transdermal patch.
    [0255] Figure 10 compares the permeation of human skin in vitro, for 24 hours, of ropivacaine of a patch containing 7.5% (w / w) of ropivacaine in Duro-Tak® 87-2677 adhesive, with an identical patch containing 15 % (w / w) of a mixture of ternary propylene glycol excipients, Capryol®90, Brij®93 (30/60/10).
    [0256] Figure 11 demonstrates the midpoint flux (| ig / cm2lr1) of ropivacaine for a transdermal patch containing 7.5% (w / w) of ropivacaine and 15% (w / w) of a ternary propylene glycol excipient mixture, Capryol® 90, Brij ®93 (30/60/10) on Duro-Tak® 87-2677 adhesive.
    [0257] Figure 12 compares the in vitro 24-hour permeation of human skin of ropivacaine from various transdermal patches of the present disclosure with a commercially available lidocaine transdermal patch (Verstatis).
    [0258] Figure 13 compares the midpoint time flux (^ g / cm2h'1) of ropivacaine for various transdermal patches of the present disclosure, with that of lidocaine from a commercially available lidocaine transdermal patch (Verstatis).
    [0259] Examples
    [0260] Solubility evaluation
    [0261] Adhesive patches only
    [0262] Initial solubility was visually evaluated in the wet adhesive prior to molding. Only mixtures in which the drug had completely dissolved were cast. The blends were cast onto an appropriate release liner and dried before laminating with an occlusive backing membrane, a small portion being laminated with a release liner. This provided a patch section that could easily be prepared for microscopic evaluation (by transfer to a glass slide). The solubility in the dry adhesive mixture was evaluated visually and by polarized microscopy. The presence of precipitate indicated that the drug loading was above saturation.
    [0263] Duro-Tak® adhesives 87-2677, 87-900A and 87-2074 were chosen as lead adhesives based on their solubility for ropivacaine. The solubilities were> 7.5 <10% (p / p),> 4 <5% (p / p) and> 12 <14% (p / p) respectively, as indicated in table 1 below:
    [0264] Table 1 - Selected pharmaceutically acceptable adhesives and their solubility (% w / w) for ropivacaine
    [0266]
    [0267]
    [0270] Improved solubility with excipients
    [0271] Combinations of adhesive and individual excipients or mixtures of excipients were studied in order to improve the solubility of ropivacaine and therefore possibly increase its rate of administration from the transdermal patch. Furthermore, the inclusion of one or more excipients in the pharmaceutical formulation, including penetration enhancers and hydrophilic materials, proved advantageous in order to improve skin permeation.
    [0272] A series of excipients were selected for the investigation of the solubility of ropivacaine, as seen in Table 2 below. Approximate solubilities were visually assessed by gradual addition of ropivacaine to a known volume of excipient at room temperature until saturation was observed.
    [0273] Table 2 - Solubility of ropivacaine (% w / v) in candidate excipients
    [0278] Other excipients were evaluated for ropivacaine solubility and compatibility with Duro-Tak® 87-900A adhesive. Adhesive compatibility was evaluated by mixing ropivacaine (4% (w / w)) and excipient (5% (w / w)) with Duro-Tak® 87-900A. The mixtures that were miscible were molded to a 350 µm wet thickness on a 3M 9741 release liner and then dried and laminated with a 3M 9730 occlusive backing membrane. Successful casts showed no precipitate after 72 hours. Adhesive compatible excipients were then subjected to solubility tests according to the protocol described above, see Table 3 below:
    [0279] Table 3 - Solubility of ropivacaine (% w / v) in candidate excipients, showing compatibility with Duro-Tak®
    [0282]
    [0283]
    [0286] The ropivacaine solubilities of binary and ternary mixtures of excipients were studied in order to enhance ropivacaine release. Furthermore, it was desirable to incorporate the skin permeation properties of more than one excipient.
    [0287] Binary mixtures of Capryol 90® and Transcutol® -25/75, 50/50, 75/25 (% v / v) - were prepared and showed ropivacaine solubilities of> 3.6 <4.8% (w / v),> 4.6 < 5.6% (p / v) and> 4.6 <5.2% (p / v) respectively.
    [0288] Other binary and ternary mixtures of propylene glycol, Capryol 90® and Brij 93® seen in Table 4 on a w / w basis were prepared and shaken with excess ropivacaine in 20 ml vials for approximately 24 hours at room temperature. Aliquots of each mixture were then centrifuged, filtered, diluted (1/5000) with acetonitrile and water 50/50 and analyzed by HPLC. The ropivacaine solubilities of the binary and ternary mixtures are shown in Table 4 below:
    [0289] Table 4 - Solubility of ropivacaine (% w / v) in mixtures of binary and ternary excipients prepared on a w / w or w / w / w basis
    [0291]
    [0292] A further evaluation of solubility was performed in a variety of ternary and quaternary mixtures of excipients (ternary mixture plus additive), see Table 5. The excipients selected for the analyzes were propylene glycol, Capryol 90®, Brij 93®, Brij 98® , Tween 80® and Cremphor EL®. The excipient mixtures were prepared and their ropivacaine solubilities were recorded, according to the protocols discussed above for the binary and ternary excipient mixtures.
    [0294] Table 5 - Solubility of ropivacaine (% w / v) in ternary and quaternary mixtures of excipients prepared on a weight basis
    [0296]
    [0299] The solubility data presented in Tables 4 and 5 demonstrate flexibility in binary, ternary and quaternary mixtures to be included in adhesives.
    [0301] Preparation of transdermal patches
    [0303] Adhesive patches only
    [0305] Patch formulations were generally prepared with 4 g of adhesive (wet).
    [0307] Ropivacaine was weighed into a single container. Adhesive was then added and the container was capped. The contents of the container were mixed using a roller mixer until the mixture became homogeneous and the ropivacaine was completely dissolved. The adhesive mixture was then poured using a blade coating (Elcometer) of an appropriate wet thickness over an appropriate release liner. Except for the menthol-incorporating patches, a wet film thickness was selected to produce a dry film thickness of 70-95 µm, or appropriately 80-85 µm. Typical cast thicknesses were 450 | im for Duro-Tak® 87-2677, 350 | im for Duro-Tak® 87-900A, and 520 | im for Duro-Tak® 87-2074 adhesive blends, resulting in thicknesses of dry film that oscillate between 70-95 | im. The wet film was dried at room temperature for 15 minutes, then at 50 ° C, for 5 minutes and finally at 90 ° C, for 10 minutes. The films were laminated with a 3M 9730 occlusive polyester film laminate. Patches incorporating menthol were cast at a lower wet thickness, typically 240-400 µm, and suitably 240 µm. These films were dried for 1 hour at room temperature, then for 5 or 10 minutes at 50 ° C. Suitably the patches were dried at 50 ° C, for 5 minutes. Dry films ranged from 45 to 78 µm, suitably about 45 µm. The thinner films subjected to shorter drying times at 50 ° C greatly reduced the loss of the volatile menthol component. Films incorporating menthol were laminated with a 3M 9730 occlusive polyester film laminate.
    [0309] Film thicknesses were measured using a digital micrometer. The thickness of the patch was measured at five locations and the thickness of the release liner / support membrane was measured at three locations. The mean film thickness was determined by subtracting the mean thickness of the release liner / support membrane from the mean thickness of the patch.
    [0311] The drug in adhesive mixes for Duro-Tak® 87-2677 adhesive required the addition of isopropyl alcohol (1 g before the addition of 4 g of adhesive) prior to molding to reduce the viscosity of the mix and aid solvation. This additional solvent would be removed during drying.
    [0313] Table 6 below provides an example of a wet mold adhesive mix.
    [0314] Table 6 - Wet Molding Mix - 4% Ropivacaine in Duro-Tak® 87-900A
    [0316]
    [0319] Duro-Tak® 87-2677 and Duro-Tak® 87-900A demonstrated compatibility with 3M 9741 Release Coating (fluoropolymer coated polypropylene film). Duro-Tak® 87-2074 demonstrated compatibility with 3M 1022 Release Coating (fluoropolymer coated polypropylene film).
    [0320] A range of ropivacaine adhesive patches prepared according to the above protocol is provided in Table 7 below:
    [0321] Table 7 - Ropivacaine (API) in transdermal patch adhesive compositions
    [0326] Adhesive plus one or more excipients
    [0327] All formulations were made with 4 g of adhesive. The charges of other constituents (prepared as w / w), such as excipients, were adjusted for percent adhesive solids so that the patch charges were relative to the weight of the dry adhesive.
    [0328] Ropivacaine was weighed into a single container. The one or more excipients were added followed by the adhesive and the container was capped. Isopropyl alcohol was added prior to addition of adhesive for preparations using Duro-Tak® 87-2677. The contents of the container were then mixed using a roller mixer until a homogeneous mixture was obtained and the ropivacaine was completely dissolved. Mold thicknesses were adjusted to account for the inclusion of the excipient blend where appropriate. The blends were molded, dried and laminated according to the protocols described for adhesive formulations only.
    [0329] A transdermal patch containing 7.5% (w / w) ropivacaine and 5% (w / w) Transcutol® was successfully prepared according to the above protocol using Duro-Tak® 87-2677 adhesive, 3M 9741 release liner and membrane. occlusive holder 3M 9730.
    [0330] Table 8, below, provides a variety of other transdermal patches prepared according to the above protocol, each containing a single excipient.
    [0331] Table 8 - Ropivacaine (API) in transdermal patches containing adhesive and 1 excipient
    [0333]
    [0336] A binary excipient mixture containing propylene glycol and Brij®93 demonstrated good compatibility with Duro-Tak® 87-900A adhesive. A patch was prepared containing 10% propylene glycol, 2% Brij®93 (w / w) and 4% ropivacaine.
    [0337] Transdermal patches containing a ternary mixture of excipients were prepared according to the above protocol. Table 9 below provides an example of a wet molding mix containing an adhesive and a ternary excipient mix:
    [0338] Table 9 - Wet molding mix - 6.5% (w / w) ropivacaine, 35% (w / w) [30/60/10]
    [0339] Propylene Glycol / Capryol®90 / Brij®93 in Duro-Tak® 87-2677
    [0341]
    [0344] More transdermal patch formulations were prepared containing adhesive and a ternary mixture of excipients, as shown in Table 9 below:
    [0345] Table 9 - Ropivacaine (API) in transdermal patches containing adhesive and a ternary mixture of excipients
    [0347]
    [0348] Transdermal patches containing other ternary or quaternary mixtures of excipients were also prepared according to the above protocol, see Tables 10 and 11 below:
    [0350] Table 10 - Ropivacaine (API) in transdermal patches containing adhesive and a ternary or quaternary mixture of excipients
    [0352]
    [0355] Table 11 - Ropivacaine (API) in transdermal patches containing adhesive and a ternary or quaternary mixture of excipients
    [0357]
    [0360] EVA membrane release studies
    [0362] Release studies were performed for selected transdermal patches and saturated aqueous solutions. For the transdermal patches, circular samples (10 mm diameter) were perforated and applied to 3M 9702 CoTran® (9% EVA) membranes mounted in horizontal Franz-type diffusion cells. Saturated aqueous solutions were prepared at 32 ° C (mixing time> 18-24 hours). To avoid depletion of the donor phase, excess ropivacaine was added to the saturated solution when applied (1 ml) to 3M 9702 CoTran® membranes (9% EVA) and the donor chambers were occluded. The receptor medium used was Walpole acetate buffer pH 4. The cells were immersed in a thermostatically controlled water bath at 32 ° C ± 0.5 ° C and the receptor phase was continuously stirred with a magnetic tracker. Ropivacaine and lidocaine permeation through the EVA membrane was measured at eight intervals for 48 hours (typically 1, 2, 4, 6, 8, 12, 24, and 48 hours from dosing). Each sample was placed in a pre-labeled 200 µl glass vial (gold grade, Chromacol®) and a PTFE cap was applied. If analysis could not be performed immediately, samples were frozen at -20 ° C pending analysis. The liquid removed in each sample was replaced with fresh, temperature-equilibrated blank receptor medium. Samples from the receptor phase were analyzed for the presence of ropivacaine by HPLC and permeated amounts (pg / cm2) were calculated.
    [0364] Appropriate calibration plots were constructed using standard solutions prepared in Walpole acetate buffer pH 4. Five level calibrations ranged from 0.1 to 50 pg / ml of ropivacaine or lidocaine. The limit of quantification (LOQ) was the area for calibration level 1 (0.1 pg / ml) and any result below the LOQ was classified as a zero result. A quality assurance (QA) sample (calibration level 4, 10 pg / ml) was included in each analytical run.
    [0366] Adhesive patches only
    [0367] Figure 1 compares the 48 hour permeation of ropivacaine from the transdermal patch formulation provided in Table 7, together with a saturated aqueous solution of ropivacaine and a buffer solution of saturated ropivacaine citrate acetate at pH 5, using a 9% EVA membrane ((3M 9702).
    [0369] Adhesive plus one or more excipients
    [0371] Figure 2 suggests that the ropivacaine permeation rate of 4% (w / w) of ropivacaine in Duro-Tak® 87-900A is greater than that of 7.5% (w / w) of ropivacaine in Duro-Tak patch. ® 87-2677 containing 5% (w / w) of Transcutol®.
    [0373] Figure 3 compares the permeation, during 48 hours, of ropivacaine of a simple patch of ropivacaine in adhesive (Duro-Tak® 87-2677), with one that contains 15% (w / w) of a ternary mixture of propylene glycol, excipients Capryol®90, Brij®93 (30/60/10). Improved permeation is observed for the patch containing the ternary mixture of excipients.
    [0375] Figure 4 compares the 48 hour permeation of ropivacaine from selected transdermal patch formulations provided in Table 10, containing 15% (w / w) ternary / quaternary mixtures of excipients. All patches tested demonstrated similar permeability characteristics.
    [0377] Figure 5 compares the 48 hour permeation of ropivacaine from selected transdermal patch formulations provided in Table 11 to a transdermal patch containing an increased amount of ropivacaine. The results demonstrate that for patches having a higher amount of excipient mixture, better permeation can be achieved using reduced amounts of dissolved ropivacaine.
    [0379] In vitro human skin permeation studies
    [0381] In vitro human skin permeation studies were performed for selected transdermal patches and saturated aqueous solutions. For patches, circular specimens (10mm diameter) were perforated and applied to human epidermal membranes (excess abdominal surgical tissue from 3 donors, n = 6) mounted on horizontal Franz-type diffusion cells. Saturated aqueous solutions were prepared at 32 ° C (mixing time> 18-24 hours). To avoid depletion of the donor phase, an excess of ropivacaine or lidocaine was added to the saturated solution when applied (1 ml) to the skin in vitro. Donor chambers were occluded. The receiving medium was 25/75 (v / v) ethanol / phosphate buffered saline pH 7.4 (EPBS) and provided immersion conditions for test permeants (<10% saturated). The skin surface temperature was maintained at 32 ° C ± 1 ° C by immersing the cells in a thermostatically controlled water bath (at 37 ° C ± 0.5 ° C). The receiving medium was continuously stirred with a magnetic follower. Ropivacaine permeation through the skin membrane was measured at five time points over 24 hours. Receiver phase samples were analyzed for activity by HPLC and permeated amounts (pg / cm2) and mean time point flux (rate of administration, pg / cm2 / h) were calculated. The data of the mean ± standard error (SE) are presented.
    [0383] The separation was carried out on a C18 HPLC column, 4 pm, 150 x 4.6 mm. An isocratic method was used and the mobile phase was acetonitrile / H2O 35/65 (v / v) plus 10 mM sodium heptane sulfonate and 0.1% acetic acid. The flow rate was 1 ml / min and the run time was 10 minutes per sample. A 20 µl full circuit injection was used for all samples and the column oven temperature was 35 ° C. Discrete wavelengths at 224 nm (Xmax and wavelength used for quantitation) were collected and 263 nm plus 210-310 nm UV scan data were collected for peak identification purposes. The retention time for ropivacaine was ~ 7.0 minutes and ~ 4.6 minutes for lidocaine. When necessary, samples were diluted in the calibration range (0.1 - 50 pg / ml).
    [0385] Adhesive patches only
    [0387] Figure 6 demonstrates the poor in vitro human skin permeation properties of a saturated ropivacaine solution versus a saturated lidocaine solution (both solutions contained excess solid).
    [0388] Figure 7 compares the permeation of human skin in vitro, for 48 hours, of ropivacaine from a patch containing 7.5% (w / w) of ropivacaine in Duro-Tak® 87-2677 adhesive, with a simple solution saturated with ropivacaine. (more excess solids). The effect of removing the patch after 24 hours is clearly shown (release of approximately 4 pg / cm2 from the skin over the next 24 hours).
    [0390] Figure 8 demonstrates the permeation of human skin in vitro, for 24 hours, of ropivacaine from a patch containing 4% (w / w) ropivacaine in Duro-Tak® 87-900A adhesive. Comparison of these data with 7.5% (w / w) ropivacaine in Duro-Tak® 87-2677 adhesive showed similar in vitro human skin permeability characteristics for both patches.
    [0392] Figure 9 demonstrates the midpoint flow time (pg / cm2h'1) for a 4% (w / w) ropivacaine in the Duro-Tak® 87-900A transdermal patch.
    [0393] Adhesive plus one or more excipients
    [0395] Table 12, below, provides the 24-hour in vitro human skin permeation values of ropivacaine from a patch containing 7.5% (w / w) ropivacaine in Duro-Tak® 87-2677 adhesive, with an identical patch containing 15% (w / w) of a ternary mixture of ternary propylene glycol excipients, Capryol®90, Brij®93 (30/60/10). Permeation values for a 4% (w / w) ropivacaine in Duro-Tak® 87-900A adhesive are also provided.
    [0397] Table 12 - Ropivacaine in vitro human skin permeation from ternary mixture patches of excipients and adhesives only
    [0399]
    [0402] Referring to Table 12, Figure 10 compares the 24-hour in vitro permeation of human skin of ropivacaine from a patch containing 7.5% (w / w) ropivacaine in Duro-Tak® 87-2677 adhesive, with an identical patch. containing 15% (w / w) of a ternary mixture of propylene glycol excipients, Capryol®90, Brij®93 (30/60/10). Better permeation of human skin in vitro is observed for the patch containing the ternary mixture of excipients.
    [0404] Referring to Table 12, Figure 11 demonstrates the midpoint flow time (pg / cm2h-1) for a transdermal patch containing 7.5% (w / w) ropivacaine and 15% (w / w) of a ternary mixture of excipients propylene glycol, Capryol®90, Brij®93 (30/60/10) in Duro-Tak® 87-2677 adhesive.
    [0406] Table 13, below, provides 24-hour in vitro human skin permeation values of ropivacaine from patches containing ternary and quaternary mixtures of excipients, with a commercially available lidocaine transdermal patch (Verstatis).
    [0408] Table 13 - In vitro human skin permeability from ropivacaine and lignocaine transdermal patches
    [0410]
    [0413] Referring to Table 13, Figure 12 compares the 24-hour in vitro permeation of human skin of ropivacaine from certain transdermal patches containing ternary and quaternary mixtures of excipients, with a commercially available lignocaine transdermal patch (Verstatis) .
    [0414] Referring to Table 13, Figure 13 compares the midpoint time flux (| ig / cm2lr1) for certain transdermal patches containing ternary and quaternary mixtures of excipients, and a commercially available lignocaine transdermal patch (Verstatis).
    [0416] Table 14, below, provides in vitro human skin apparent steady-state flux values for ropivacaine, for either 3-12 or 4-12 hours, of patches containing either drug-in-adhesive alone or with mixtures. ternary and quaternary excipients. Flow values for saturated aqueous solutions of ropivacaine and lidocaine are also provided. Flow values were calculated using a linear fit of permeation data (as presented in Figures 7, 8, 10, and 12) during apparent steady-state delivery and correlation coefficients are provided (r2> 0.998 in all parts).
    [0418] Table 14 - In vitro human skin apparent steady-state flux values of ropivacaine transdermal patches and saturated aqueous solutions of ropivacaine and lignocaine
    [0420]
    权利要求:
    Claims (17)
    [1]
    1. A transdermal patch comprising a pharmaceutical formulation, said formulation comprising:
    (i) ropivacaine;
    (ii) a pharmaceutically acceptable adhesive;
    and additionally a penetration enhancer selected from fatty acid esters and ethers of sugar, C8-C18 fatty alcohol, azone, oleic ethers, terpenes and ethoxyethanols;
    and additionally a hydrophilic material;
    and additionally a carrier oil selected from sorbitan monooleate, sorbitan trioleate, carboxy / capric acid triglycerides, propylene glycol dicaprylate / dicaprate, ethoxy diglycol, propylene glycol monocaprylate, glycerol monooleate, lanolin, acetylated lanolin, polyethylene glycol monooleate, lanolin glycerol caprate, propylene glycol laurate and / or capric acid mono or diglycerides;
    wherein the patch further comprises a support membrane.
    [2]
    2. A transdermal patch according to claim 1, wherein the amount of penetration enhancer, hydrophilic material and carrier oil present in the pharmaceutical formulation is 10% (w / w) to 40% (w / w).
    [3]
    3. A transdermal patch according to any preceding claim, wherein the pharmaceutical formulation has a permeation rate of ropivacaine in human skin in vitro that is:
    (a) more than 1.8 | ig cm-2 h-1;
    [4]
    4. A transdermal patch according to any preceding claim, wherein the amount of ropivacaine in the pharmaceutical formulation is:
    (a) between 3 and 20% w / w;
    [5]
    5. A transdermal patch according to any preceding claim, wherein the adhesive:
    (a) has a ropivacaine solubility greater than 2.5% w / w at room temperature; me
    (b) is selected from acrylate / polyacrylate materials, rubbers, or silicones; me
    (c) is an acrylate copolymer material or an acrylate-vinyl acetate material.
    [6]
    6. A transdermal patch according to any of the preceding claims, wherein the carrier oil is present in the pharmaceutical formulation in an amount between 2.5 and 35% w / w.
    [7]
    7. A transdermal patch according to claim 6, wherein:
    (a) the carrier oil is present in the pharmaceutical formulation in an amount between 9 and 21% w / w or in an amount between 12 and 21% w / w; me
    (b) the carrier oil is propylene glycol monocaprylate, propylene glycol laurate and / or capric acid mono or diglycerides, where optionally the carrier oil is propylene glycol monocaprylate.
    [8]
    8. A transdermal patch according to any of the preceding claims, wherein the penetration enhancer is present in the pharmaceutical formulation in an amount between 1.4 and 15% w / w.
    [9]
    9. A transdermal patch according to claim 8, wherein:
    (a) the penetration enhancer is present in the pharmaceutical formulation in an amount between 1.5 and 4% w / w; me
    (b) the penetration enhancer is selected from the group consisting of polyoxyethylene oleyl ether, 2- (2-ethoxyethoxy) ethanol, and menthol; me
    (c) the penetration enhancer is polyoxyethylene oleyl ether.
    [10]
    10. A transdermal patch according to any of the preceding claims, wherein the hydrophilic material is present in the pharmaceutical formulation in an amount between 1.5 and 20% w / w.
    [11]
    11. A transdermal patch according to claim 10, wherein:
    (a) the hydrophilic material is present in the pharmaceutical formulation in an amount between 6 and 11% w / w; me (b) the hydrophilic material is selected from the group consisting of short chain water soluble esters of citric acid, acetic acid, and alcohols, including diols and polyols; me
    (c) the hydrophilic material is propylene glycol.
    [12]
    12. A transdermal patch according to any one of claims 1 to 5, comprising propylene glycol monocaprylate, propylene glycol and polyoxyethylene oleyl ether present in an amount between 10 and 40% w / w in the pharmaceutical formulation.
    [13]
    13. A transdermal patch according to claim 12, wherein:
    (a) propylene glycol monocaprylate, propylene glycol and polyoxyethylene oleyl ether are present in the pharmaceutical formulation in an amount between 15 and 35% w / w or in an amount of 35% w / w; me
    (b) The pharmaceutical formulation further comprises an additive selected from the group consisting of nonionic surfactants, hydrophilic surfactants, terpenes, and membrane disruptors, where optionally the additive is selected from the group consisting of menthol and diethylene glycol monoethyl ether.
    [14]
    A pharmaceutical formulation suitable for inclusion in a transdermal patch according to claim 1, wherein said formulation is as defined in any preceding claim.
    [15]
    15. A pharmaceutical formulation according to claim 14 or a transdermal patch according to any one of claims 1 to 13 for use as a medicine.
    [16]
    16. A pharmaceutical formulation according to claim 14 or a transdermal patch according to any one of claims 1 to 13 for use:
    (a) in the treatment of pain; or
    (b) in the treatment of one or more of the neuropathic and nociceptive pain.
    [17]
    17. A method of preparing a pharmaceutical formulation according to claim 14, said method comprising mixing:
    (i) ropivacaine;
    (ii) an adhesive according to claim 1 or 5; and
    (iii) three excipients selected from a penetration enhancer according to claim 1, 8 or 9, a hydrophilic material according to claim 1, 10 or 11, and a carrier oil according to claim 1, 6 or 7.
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    同族专利:
    公开号 | 公开日
    CA2926146A1|2015-04-16|
    ES2819211T3|2021-04-15|
    US20160235689A1|2016-08-18|
    EP3054918A1|2016-08-17|
    WO2015052183A1|2015-04-16|
    GB201317718D0|2013-11-20|
    EP3054918B1|2020-09-02|
    EP3054918B9|2021-07-14|
    US10166199B2|2019-01-01|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GBGB1317718.3A|GB201317718D0|2013-10-07|2013-10-07|Novel formulation|
    PCT/EP2014/071437|WO2015052183A1|2013-10-07|2014-10-07|Novel formulation|
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