WO2008022128A2 - Transdermal delivery of meptazinol - Google Patents
Transdermal delivery of meptazinol Download PDFInfo
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- WO2008022128A2 WO2008022128A2 PCT/US2007/075902 US2007075902W WO2008022128A2 WO 2008022128 A2 WO2008022128 A2 WO 2008022128A2 US 2007075902 W US2007075902 W US 2007075902W WO 2008022128 A2 WO2008022128 A2 WO 2008022128A2
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- WIPO (PCT)
- Prior art keywords
- agents
- meptazinol
- salt
- transdermal
- transdermal device
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Definitions
- This invention relates to the administration of meptazinol for analgesic purposes and more particularly to a method and device for administering meptazinol to a patient in need thereof over an extended period of time at an essentially constant rate while avoiding first pass metabolism.
- Meptazinol is a mixed agonist-antagonist analgesic with specificity for the m ⁇ l opioid receptor and its chemical structure is defined by formula (I) below:
- Meptazinol has been shown to have a negligible clinical dependency liability from both formal clinical investigation and the lack of reported instances of street use/abuse.
- the lack of addictive potential for meptazinol was first reported in 1987 by the internationally reknowned investigator, Dr. Don Jasinski (Lexington, Kentucky). This property distinguishes meptazinol from many other strong analgesics such as fentanyl (e.g. Duragesic), pentazocine, oxycodone (e.g. Oxycontin, Percocet), and morphine which are all classified as "Controlled Drugs" with consequent prescription/ dispensation restrictions.
- fentanyl e.g. Duragesic
- pentazocine e.g. Oxycontin, Percocet
- morphine e.g. Oxycontin, Percocet
- Meptazinol also has many clinical advantages over the more conventional opioid analgesics which include causing minimal respiratory depression, causing minimal sedation and lacking a constipating effect.
- meptazinol a favored obstetric analgesic to avoid infant respiratory distress.
- Other analgesics given during labor such as pethidine and diacetylmorphine can cause significant infant respiratory depression giving rise to the so-called grey baby syndrome often necessitating the use of a narcotic antagonist such as naloxone to reverse this effect.
- Causing minimal sedation is advantageous in treating chronic pain conditions and assists a patient in conducting a normal daily life.
- the sedation associated with other analgesics frequently induces lethargy and a dramatic reduction in the quality of life - with the patients entering a near twilight world.
- constipation is an important property in treating chronic pain.
- the constipation commonly associated with the other strong analgesics can be a most distressing condition especially for the older patient.
- the lack of a constipating effect for meptazinol represents an important advantage over other strong analgesics such as pethidine.
- meptazinol which is effected by a simple one-step glucuronidation process with the ensuing inactive, water-soluble conjugate being filtered at the kidney.
- This process of conjugative metabolic clearance is not as affected by age as some other clearance mechanisms such as direct filtration of the active entity at the kidney or oxidative metabolic clearance as required for example by pethidine.
- use of meptazinol has been restricted by two major disadvantages: (1) low oral biovailability; with reported mean values lying between 4-9% as the result of extensive first pass metabolism and (2) a propensity, in common with other strong analgesics, to cause nausea and emesis.
- Transdermal delivery of strong analgesics in recent years has proven to be a useful means of overcoming many of the problems associated with their oral administration. Modulating the sharp rise in plasma drug levels, usually seen after oral dosing, may serve to minimize the emesis associated with the comparatively high C max values resulting from rapid absorption. In the specific case of meptazinol, avoidance of emesis becomes very much more important to minimize loss of drug trapped in the stomach by its inhibitory effects on gastric emptying.
- Transdermal delivery also provides a means of avoding the first pass metabolism through the liver which in the case of meptazinol removes up to 98.1% of an oral dose.
- Such a high first pass elimination of the drug inevitably leads to large inter and intra subject variability in achieved plasma drug concentrations.
- oral bioavailablity varied from 1.89% to 18.5%, almost a ten-fold range.
- Meptazinol is inherently not a potent drug when administered orally, requiring 200 mg dosages every four to six hours. Even when the poor bioavailability of meptazinol is factored in, the average daily required dose for an effective dose would be -50 -100 mg which approximates to a flux rate of ⁇ 83-166ug/cm 2 /h from a 25 cm 2 transdermal patch. Such inherently high flux rates are not usually seen with other transdermal products and so represents a significant technical challenge.
- transdermal delivery systems which may generically incorporate meptazinol have been referred to in the art, e.g. Oshlack et al. (U.S. Patent 6,716,449 - hereinafter "Oschlack"), but there is no evidence in the art that these systems were capable of delivering meptazinol at the necessary high flux rates.
- Oschlack makes reference to maintaining prior art defined concentration levels or release rates while decreasing the amount of dosing by a factor of about 100 to about 1000, i.e. Oschlack does not indicate how the flux rate of meptazinol could be achieved by transdermal delivery.
- Skin flux can be determined by multiplying the permeability coefficient (k p in cm/h) of meptazinol by the aqueous solubility of meptazinol.
- a non- addictive mixed agonist-antagonist analgesic such as meptazinol
- delivery system and "delivery vehicle” as used herein is meant to describe a method of providing meptazinol via transdermal transportation which avoids "first pass metabolism".
- First pass metabolism refers to the reduction of bioavailability of a drug, e.g. meptazinol, because of the metabolic or excretory capacity of the liver which is a common problem associated with oral administration.
- Transdermal delivery is distinct from parenteral or delivery by injection in that the latter bypasses the stratum corneum, epidermal and dermal layers of the skin and delivers the active agent directly to the subcutaneous layer.
- Transdermal delivery as used herein is meant to describe a process wherein an active agent, e.g. meptazinol or a derivative thereof, contacts and passes through or permeates through one or more of the stratum corneum, epidermal and dermal layers of the skin. This passing through or permeation through can be accomplished via: (1) transcellular penetration (across the cells);
- transappendageal penetration via hair follicles, sweat and sebum glands, and pilosebaceous apparatus.
- the invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof for meptazinol (including those of the weakly acidic phenolic function as well as those of the weakly basic azepine nitrogen). Furthermore, it encompasses various other meptazinol precursors derived by covalent linkage to the phenolic function such as ethers esters and glycosides described later.
- the pharmaceutically acceptable salts (of the phenol) include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine guanidine & //-substituted guanidine salts, acetamidine & //-substituted acetamidine salts, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.
- metal salts such as sodium salt, potassium salt, cesium salt and the like
- alkaline earth metals such as calcium salt, magnesium salt and the like
- organic amine salts such as triethylamine guanidine & //-substituted guanidine salts, acetamidine & //-substituted acetamidine salts,
- Pharmaceutically acceptable salts include, but are not limited to inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as trifluoroacetate, maleate, and the like; sulfonates such as methanesulfonate, ethanesulphonate, benzenesulfonate, p-toluenesulfonate, camphor sulphonate and naphthalenesulphonate, and the like; amino acid salts such as alaninate, asparginate, glutamate and the like.
- inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like
- organic acid salts such as trifluoroacetate, maleate, and the like
- sulfonates such as methanesulfonate, ethanesulphonate, benzenesulfonate, p-to
- Meptazinol is a chiral molecule containing one stereogenic center at the C-3 position of the azepine and can therefore exist as two enantiomeric forms (R and S stereoisomers)
- Reference to meptazinol for the purposes of this invention encompasses each enantiomer and mixtures thereof including a racemic mixture (racemate) of the enantiomers unless otherwise indicated.
- Figure 1 illustrates the comparative permeation of meptazinol free base and a number of its salts through human skin.
- Figure 2 shows the skin flux of the various salts of meptazinol though human skin.
- the present invention is directed to a delivery system which delivers a pharmacologically effective amount of meptazinol for pain or to provide analgesic relief.
- delivery systems include but are not limited to those means which enable delivery of meptazinol or salt form thereof via parenteral injection, pulmonary absorption, topical application, sublingual administration and rectal administration.
- Parenteral injections include delivery via intravenous injection, subcutaneous injection, intramuscular injection, intraarterial injection and intrathecal injection. Pulmonary absorption includes the use of inhalants and aerosols.
- Topical administration includes administration via: (1) mucous membranes which includes but is not limited to mucous membranes of the conjunctiva, nasopharnyx, oropharynx, vagina, colon, urethra and urinary bladder; (2) the skin (which includes topical or transdermal delivery); and (3) the eye.
- the delivery vehicle is for topical administration to the skin and includes but is not limited to a transdermal device, a cream, a lotion or an ointment which delivers a pharmacologically effective amount of meptazinol for pain or to provide analgesic relief.
- the delivery vehicle is a transdermal device.
- the transdermal device is intended to deliver the pharmacologically effective amount of meptazinol either in a manner which: (1) controls the rate of drug delivery to the skin or (2) allows the skin to control the rate of drug absorption.
- the transdermal device for the transdermal delivery of an effective amount of meptazinol to provide analgesic relief comprises of:
- a device which comprises of (i) a backing layer; (ii) a reservoir layer for the salt form of meptazinol or a salt of a meptazinol precursor;
- a pharmaceutically effective carrier (c) a pharmaceutically effective carrier.
- the backing layer, reservoir layer, control membrane, adhesive and protective peel strip can be formed using conventional teachings in the art such as those referred to in U.S. Patent 6,818,226 (Dermal penetration enhancers and drug delivery systems involving same); U.S. 6,791,003 (Dual adhesive transdermal drug delivery system); U.S. Patent 6,787,149 (Topical application of opioid analgesic drugs such as morphine); U.S. Patent 6,716,449 (Controlled release compositions containing opioid agonist and antagonist); U.S. Patent 5,858,393 (Transdermal formulation); U.S. Patent 5,612,382 (Composition for percutaneous absorption of pharmaceutically active ingredients); U.S.
- Patent 5,464,387 Transdermal delivery device
- U.S. Patent 5,023,085 Transdermal flux enhancers in combination with iontophoresis in topical administration of pharmaceuticals
- U.S. Patent 4,891,377 Trandermal delivery of the narcotic analgesics etorphine and analogs
- U.S. Patent 4,654,209 Preparation of percutaneous administration, each of which is incorporated by reference.
- the delivery device for topical administration is a transvaginal ring such as those described in U.S. Patents 6,503,190; 6,394,094;
- a vaginal ring has a body dimensioned to allow for insertion into the vagina, e.g. a cylindrical shape although other shapes can also be used, and can be configured by those of ordinary skill in the art to deliver the meptazinol salts of the invention. Delivery of the meptazinol in this manner may effect pain relief by virtue of the drug's historically reported local anaesthetic activity - about 1/10 th of that of lidocaine - or by a centrally mediated mechanism. Such an application could, for example, find application in the period immediately following gynaecological surgery.
- the non-controlling membrane comprises Solupor 10P05 A (manufactured by DSM) and the adhesive DURO-TAK 87-608 A
- the transdermal device may constitute a so-called "drug in adhesive” or matrix patch in which the drug is intimately distributed in an appropriate pressure sensitive adhesive such as but not limited to the DURO-TAK polyacrylates.
- the transdermal device of the invention is able to provide long lasting relief and is an improvement from the prior art which require 4-6 dosages per day.
- the transdermal device is able to provide up to about 8 hours of analgesic relief; in another embodiment of the invention, the transdermal device is able to provide about 8 to about 24 hours of relief; and in a further embodiment of the invention, the transdermal device is able to provide from about 24 hours of relief to about 168 hours of relief.
- the transdermal device Given the low solubility of the free base form of meptazinol free base (0.17 mg/mL in aqueous solution), it may be advantageous to derivatize the meptazinol to form a precursor compound which will degrade into meptazinol when traversing the layer(s) of the skin.
- another embodiment of the invention is the delivery of meptazinol transdermally which is achieved by a transdermal device which contains a precursor of meptazinol which includes but is not limited to meptazinol esters, glycosides, salts of meptazinol or mixtures thereof.
- Precursors of meptazinol are compounds which undergo a transformation in vivo to produce meptanizol (e.g. cleavage of an ester bond, glycolysis, formation of the free base from the salt).
- Meptazinol esters, ethers and glycosides of the invention are compounds of the formula (II):
- R is an acyl group, a mono-, oligo- or poly-saccharide, or salts of mono-, oligo- or poly-saccharides.
- Oligo- or poly-saccharide indicates a saccharide comprised of 2-10 monosaccharide units which are covalently bonded together
- R When R forms an ether, one embodiment of the invention is where R is a substituted or unsubstituted Ci-Ci 2 -alkyl or substituted or unsubstituted aryl. In another embodiment of when R is an ether, R is a substituted or unsubstituted Ci-C 4 -alkyl or substituted or unsubstituted phenyl. In both embodiments, the substituents are selected from the group consisted of halogen, Ci-C 4 -alkyl, and Ci-C 4 -alkoxy.
- R is a monosaccharide
- R is selected from the group consisting of erythrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrosyl, glucosyl, glucosylamino, mannosyl, gulosyl, idosyl, galactosyl, galactosylamino, talosyl and salts thereof; another embodiment is where R is glucosyl, glucosylamino, galactosyl or galactosylamino and salts thereof; and yet another embodiment of the invention is where R is glucosyl and salts thereof.
- R is an oligosaccharide
- R is selected from the group consisting of lactose, sucrose, trehalose, Lewis a trisaccharide, 3'-O- sulfonato Lewis a, Lewis b tetrasaccharide, Lewis x trisaccharide, Sialyl Lewis x, 3'-O- sulfonato Lewis x, Lewis y tetrasaccharide and salts thereof.
- R is a polysaccharide
- R is selected from the group consisting of chitin, chitosan, cyclodextrin, dextran and pullulan; another embodiment of the invention is where the cyclodextrin is ⁇ -, ⁇ - or ⁇ -cyclodextrin; yet another embodiment of the invention is where the cyclodextrin is ⁇ -cyclodextrin, dimethyl- ⁇ - cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin.
- cyclodextrin have a cavity which can accommodate the inclusion of a compound such as meptazinol
- another embodiment of the invention is where the cyclodextrins described in R above can also be added to meptazinol to form an inclusion complex rather than being linked covalently.
- the meptazinol precusor is a salt and R is hydrogen but absent, whereby the oxygen is negatively charged;
- the salt form is selected from the group consisting of sodium, potassium, caesium , calcium, magnesium, guanidine & //-substituted guanidine salts and acetamidine & //-substituted acetamidine salts triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine.
- R is hydrogen - or one of the aforementioned substituents - and the azepine nitrogen is positively charged and linked with hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, ethanesulphonate, benzenesulfonate, p-toluenesulfonate, naphthalene sulphonate. camphor sulfonate, arginate, alaninate, asparginate, glutamate and mixtures thereof.
- the skin flux of fentanyl free base is up to five times faster than the salt form.
- the free base shows unexpectedly poor flux in comparison to the various salt forms.
- meptazinol hydrochloride has a substantially greater flux than the free base.
- an additional analgesic can be added to the transdermal device.
- analgesics include but are not limited to ethanol, non- steroidal anti-inflammatory drugs (NSAIDs) and other compounds with anagelsic properties such as but not limited to amitriptyline and carbamazepine.
- the pharmaceutically effective carrier includes but is not limited to a solvent such as alcohol, isopropylmyristate, glycerol monooleate or a diol such as propylene glycol, or the like.
- a solvent such as alcohol, isopropylmyristate, glycerol monooleate or a diol such as propylene glycol, or the like.
- the delivery of the meptazinol or meptazinol precursor is enhanced by the use of a permeation enhancer which may also be included in the pharmaceutically effective carrier.
- suitable permeation enhancers include but are not limited to polyunsaturated fatty acids (PUFA) such as arachidonic acid, lauric acid, ⁇ -linolenic acid, linoleic acid and oleic acid; dimethylisosorbide; azones; cyclopentadecalactone; alkyl-2-(N, N-disubstituted amino)- alkanoate ester (NexAct); 2-(n-nonyl)-l,3-dioxaolane (SEPA); cod-liver oil; essential oils, glycerol monoethers derived from saturated fatty alcohols; D-limonene; menthol and menthol ethyl ether; N-methyl-2-pyrrolidone (NMP); phospholipids; squalene; terpenes; and alcohols such as methanol, ethanol, propanol and butanol.
- PUFA polyunsaturated fatty acids
- transdermal drug delivery is enhanced by iontophoresis, magnetophoresis, or sonophoresis.
- Iontophoresis involves the delivery of charged chemical compounds across the skin membrane using an applied electrical field, see e.g. "Pharmaceutical Dosage Forms and Drug Delivery Systems - Chapter 10 - Transdermal Drug Delivery Systems, Ointments, Creams, Lotions and Other Preparations", ed. by Ansel et al., Williams & Wilkins, page 360, (1995).
- Magnetophoresis involves the use of a magnetic field to enhance drug delivery to the skin, see e.g. Murthy et al., "Physical and Chemical Permeation Enhancers in Transdermal Delivery of Terbutaline Sulphate", AAPS
- Sonophoresis is the use of high-frequency ultrasound which serves to compromise the integrity of the stratum corneum layer and improve permeability of compounds through the skin.
- transdermal drug delivery may be effected using various topically applied ointments, creams, or lotions.
- these may comprise oil-in- water emulsions or water-in-oil emulsions incorporating meptazinol or meptazinol precursor in one of the preferred vehicles.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents
- the solubility (as measured in aqueous solution) of the meptazinol or meptazinol precursor is about 30 mg/mL to about 500 mg/mL; in yet another embodiment of the invention, the solubility is about 50 mg/mL to about 400 mg/mL; and in a still further embodiment of the invention, the solubility is about 75 mg/mL to about 300 mg/mL.
- the skin flux for the delivery of the meptazinol or meptazinol precursor is about 20 to about 1000 ⁇ g/cm 2 /h; in yet another embodiment of the invention, the skin flux for the delivery of the meptazinol or meptazinol precursor is about 50 to about 500 ⁇ g/cm 2 /h; and in a further embodiment of the invention is about 75 to about 250 ⁇ g/cm 2 /h.
- the pH of the environment into which the meptazinol or meptazinol precursor is released is about pH 4.0 to about pH 7.0; in another embodiment, the pH is about 4.0 to about 6.0; and in a further embodiment, the pH is about 4.0 to about 5.0.
- additional skin care ingredients may be combined with meptazinol or the meptazinol precursors for their art recognized effects, these include abrasives, absorbents, adhesives, antiacne agents, anticaking agents, anticareis agents, antidandruff agents, antifoaming agents, antifungal agents, antimicrobial agents, antioxidants, antiperspirant agents, antistatic agents, binders, buffering agents, bulking agents, chelating agents, colorants, corn/callus/wart removers, corrosion inhibitors, cosmetic astringents, cosmetic biocides, denaturants, depilating agents, drug astringents, emollients, emulsion stabilizers, epilating agents, exfoliants, external analgesics, film formers, flavoring agents, fragrance ingredients, humectants, lytic agents, occlusives opacifying agents, oxidizing agents, pesticides, pH adjusters, plasticizers, preservatives, propellant
- transdermal device in another embodiment, use of the transdermal device described hereinabove can be used to provide analgesic effects to treat systemic or localized pain to a patient in need thereof.
- FIG. 1 shows that a salt of meptazinol is surprisingly more permeable than the free base form of meptazinol.
- Figure 2 shows that surprisingly meptazinol salts formed from a stronger acid, such as the hydrochloride and trifluoroaceate salt are more rapidly absorbed than are those of weaker organic acids such as the camsylate, tosylate or maleate.
- Table 1 The data presented in Table 1 below show that under the test conditions cited above, the mean flux for the various salts tested were suitable for producing concentrations of meptazinol sufficient to produce a long-lasting effect when administered to patient in need thereof.
- Table 1 Intersubject variability in flux rates for meptazinol salts through human skin
- NB Vehicle comprised 2% oleic acid: 2% dimethyl isosorbide: 96% propylene glycol
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07840928A EP2061441A2 (en) | 2006-08-14 | 2007-08-14 | Transdermal delivery of meptazinol |
BRPI0716119-0A2A BRPI0716119A2 (en) | 2006-08-14 | 2007-08-14 | Transdermal Meptazinol Distribution. |
US12/377,287 US20100209483A1 (en) | 2005-12-21 | 2007-08-14 | Transdermal delivery of meptazinol |
JP2009524765A JP2010501001A (en) | 2006-08-14 | 2007-08-14 | Transdermal delivery of meptazinol |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US82231806P | 2006-08-14 | 2006-08-14 | |
US60/822,318 | 2006-08-14 | ||
US86211406P | 2006-10-19 | 2006-10-19 | |
US60/862,114 | 2006-10-19 | ||
US11/614,165 US20070224253A1 (en) | 2005-12-21 | 2006-12-21 | Transdermal Delivery of Meptazinol |
US11/614,165 | 2006-12-21 |
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WO2008022128A2 true WO2008022128A2 (en) | 2008-02-21 |
WO2008022128A3 WO2008022128A3 (en) | 2008-11-20 |
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PCT/US2007/075902 WO2008022128A2 (en) | 2005-12-21 | 2007-08-14 | Transdermal delivery of meptazinol |
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EP (1) | EP2061441A2 (en) |
JP (1) | JP2010501001A (en) |
WO (1) | WO2008022128A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2946776A1 (en) * | 2014-05-20 | 2015-11-25 | LTS LOHMANN Therapie-Systeme AG | Transdermal therapeutic system for the release of amitriptylin |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1539277A (en) * | 1977-09-16 | 1979-01-31 | Wyeth John & Brother Ltd | Hexahydro-1h-azepines |
GB2122895A (en) * | 1982-07-08 | 1984-01-25 | Wyeth John & Brother Ltd | Analgesic compositions |
WO2004017941A2 (en) * | 2002-08-20 | 2004-03-04 | Euro-Celtique, S.A. | Transdermal dosage form comprising an active agent and a salt and free-baseform of an antagonist |
WO2004098567A2 (en) * | 2003-04-30 | 2004-11-18 | Purdue Pharma L.P. | Tamper-resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer |
-
2007
- 2007-08-14 WO PCT/US2007/075902 patent/WO2008022128A2/en active Application Filing
- 2007-08-14 EP EP07840928A patent/EP2061441A2/en not_active Withdrawn
- 2007-08-14 JP JP2009524765A patent/JP2010501001A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1539277A (en) * | 1977-09-16 | 1979-01-31 | Wyeth John & Brother Ltd | Hexahydro-1h-azepines |
GB2122895A (en) * | 1982-07-08 | 1984-01-25 | Wyeth John & Brother Ltd | Analgesic compositions |
WO2004017941A2 (en) * | 2002-08-20 | 2004-03-04 | Euro-Celtique, S.A. | Transdermal dosage form comprising an active agent and a salt and free-baseform of an antagonist |
WO2004098567A2 (en) * | 2003-04-30 | 2004-11-18 | Purdue Pharma L.P. | Tamper-resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer |
Non-Patent Citations (2)
Title |
---|
LU M ET AL: "Synthesis and relative bioavailability of meptazinol benzoyl esters as prodrugs" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, GB, vol. 15, no. 10, 16 May 2005 (2005-05-16), pages 2607-2609, XP004877734 ISSN: 0960-894X * |
XIE ET AL: "Design, synthesis, and bioavailability evaluation of coumarin-based prodrug of meptazinol" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, GB, vol. 15, no. 22, 15 November 2005 (2005-11-15), pages 4953-4956, XP005098205 ISSN: 0960-894X * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2946776A1 (en) * | 2014-05-20 | 2015-11-25 | LTS LOHMANN Therapie-Systeme AG | Transdermal therapeutic system for the release of amitriptylin |
WO2015176800A1 (en) * | 2014-05-20 | 2015-11-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system for releasing amitriptyline |
Also Published As
Publication number | Publication date |
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WO2008022128A3 (en) | 2008-11-20 |
EP2061441A2 (en) | 2009-05-27 |
JP2010501001A (en) | 2010-01-14 |
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