WO1994009777A1 - Apport transdermique de ketorolac - Google Patents
Apport transdermique de ketorolac Download PDFInfo
- Publication number
- WO1994009777A1 WO1994009777A1 PCT/US1993/010219 US9310219W WO9409777A1 WO 1994009777 A1 WO1994009777 A1 WO 1994009777A1 US 9310219 W US9310219 W US 9310219W WO 9409777 A1 WO9409777 A1 WO 9409777A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ketorolac
- composition
- subject
- skin
- amount
- Prior art date
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- 229960004752 ketorolac Drugs 0.000 title claims abstract description 146
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title claims abstract description 142
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- KYYWBEYKBLQSFW-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O KYYWBEYKBLQSFW-UHFFFAOYSA-N 0.000 description 1
- ZILMEHNWSRQIEH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O.CCCCCC(O)=O ZILMEHNWSRQIEH-UHFFFAOYSA-N 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- RQFLGKYCYMMRMC-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O RQFLGKYCYMMRMC-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- ZTUXEFFFLOVXQE-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCC(O)=O ZTUXEFFFLOVXQE-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940019127 toradol Drugs 0.000 description 1
- 229940035321 transderm scop Drugs 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Definitions
- This invention relates to the transdermal delivery of ketorolac; and in particular to compositions and devices which provide for the transdermal delivery of therapeutically effective, systemic amounts of ketorolac, especially for sustained delivery.
- Ketorolac and its pharmaceutically acceptable salts are described in U.S. Pat. No. 4,089,969 (Syntex) and U.S. Pat. No. 4,454,151 (Syntex) , which are herein incorporated in full by reference.
- NSAID non-steroidal anti-inflammatory drug
- ketorolac exhibits anti-inflammatory, analgesic and anti-pyretic activities and is therefore useful in the treatment of inflammation, pain and/or pyrexia in mammals, particularly humans.
- the compound is also useful for treating certain ophthalmic diseases by the topical administration to the eye. See, e.g. , U.S. Patent No. 4,454,151 (Syntex).
- ketorolac i.e., ketorolac tromethamine
- Toradol ® a pharmaceutically acceptable salt of ketorolac
- a gel formulation of ketorolac is known for local topical use.
- the gel formulation which exhibits topical therapeutically effective activity, is comprised of ketorolac (or a pharmaceutically acceptable salt) , a lower alkanol, water, a thickening agent, and optionally a penetration enhancer. See, e .g. , U.S. 5,019,182 (Syntex) (which is herein incorporated in full by reference) and J. Clin. Pharmacol . (1990), Vol. 30, No. 1, pp. 82-89.
- Transdermal delivery of drugs for systemic effect offers certain advantages over intravenous, intramuscular and oral delivery.
- transdermal delivery of drugs is generally less painful for the subject than intravenous or intramuscular delivery.
- it is generally less difficult to deliver a drug transdermally than it is to deliver intravenously or intramuscularly.
- transdermal delivery of a drug offers improved compliance over oral delivery.
- ketorolac While a number of drugs such as nitroglycerine, nicotine, fentanyl, clonidine, scopolamine and estradiol have been successfully marketed in transdermal formulations and others are in development (see for example Timalol, Physostigmine, etc.), no systemically effective transdermal formulations of ketorolac have been proposed or disclosed in the art.
- an object of the present invention is to provide a composition suitable for transdermally delivering a therapeutically effective systemic amount of ketorolac to a subject in need thereof.
- a composition suitable for transdermally delivering a therapeutically effective systemic amount of ketorolac to a subject in need thereof.
- Such a composition would have minimum skin irritation upon application.
- Another object is to provide a ketorolac transdermal delivery device which would make it easier to administer ketorolac, thereby improving patient compliance, particularly with respect to the treatment of pain.
- Such a device would exhibit a rapid onset of action upon application to the subject in need thereof and would transdermally deliver, preferably in a sustained manner, a therapeutically effective systemic amount of ketorolac to the patient, with minimum irritation to the skin of the subject.
- this invention is a composition useful for transdermally delivering a therapeutically effective systemic amount of ketorolac to a subject in need thereof; wherein the composition comprises ketorolac dissolved in a biocompatible aqueous vehicle and wherein the composition exhibits a skin flux value sufficient to deliver a systemic amount of ketorolac to the subject's blood stream.
- this invention is a device for transdermally delivering a therapeutically effective systemic amount of ketorolac to a ' subject in need thereof, which device comprises: (a) a composition comprising:
- ketorolac dissolved in a biocompatible aqueous vehicle, and (ii) a gelling agent in an amount sufficient to gel the composition; wherein the composition exhibits a skin flux value sufficient to transdermally deliver a systemic amount of ketorolac to the subject's blood at a substantially constant rate throughout the delivery life of the device; (b) a reservoir for containing the composition, which reservoir is defined by:
- (c) means to maintain the side of the device opposite the backing in contact with the skin of the subject to allow for the transdermal delivery of ketorolac.
- this invention is a method of transdermally delivering a therapeutically effective systemic amount of ketorolac to a subject in need thereof, which method comprises placing a device as described above in contact with the subject's skin for a time sufficient to release the ketorolac.
- Figure 1 is a schematic, cross-sectional view of one embodiment of a device of this invention prior to its application to a subject's skin.
- Figure 2A is a top-down view of the embodiment of this invention as shown in Figure 1.
- Figure 2 B is a bottom-up view of the embodiment of this invention as shown in Figure 1.
- Figure 3 is a schematic, cross-sectional view of another embodiment of a device of this invention prior to its application to a subject's skin.
- like parts are referred to by like numerals.
- Ketorolac refers to ( ⁇ ) -5-benzoyl-2,3-dihydro-lH-pyrrolizine-l- carboxylic acid (USAN) , i.e., the compound of the following formula:
- ketorolac encompasses the free acid and pharmaceutically acceptable salts and esters thereof.
- ketorolac will be present in the invention as the tromethamine salt, i.e., as ketorolac tromethamine.
- ketorolac may exist as a single stereoisomer or as a racemic or non-racemic mixture of the stereoisomers.
- the term "ketorolac” encompases all the stereoisomers, racemic mixtures and non- racemic mixtures thereof.
- the racemic mixture of ketorolac or its pharmaceutically acceptable salts is preferred.
- Alkyl refers to a straight or branched, saturated or unsaturated, aliphatic hydrocarbon radical, having the number of carbon atoms specified, or if no number is specified, having from one to eighteen carbon atoms, e.g. , ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, hexyl, octyl, iso-decyl, 6-methyldecyl, 1,3-butadiene, 1,3,5,7-octatetrene, and the like.
- “Lower alkanol” refers to a straight or branched aliphatic hydrocarbon having from two to six carbon atoms, wherein one hydroxyl radical is attached thereto, e. g. , ethanol, isopropanol, n-butanol, and the like.
- Alkanoic acid refers to a straight or branched, saturated or unsaturated, aliphatic hydrocarbon of the formula R_C(0)OH where R. is an alkyl radical as defined above, having the number of carbon atoms specified, or if no number is specified, having from four to eighteen carbon atoms, e.g., butanoic acid (butyric acid), hexanoic acid (caproic acid) , octanoic acid (caprylic acid) , decanoic acid (capric acid) , dodecanoic acid (lauric acid) , tetradecanoic acid (myristic acid) , hexadecanoic acid (palmitic acid) , octadecanoic acid (stearic acid) , and the like.
- R. is an alkyl radical as defined above, having the number of carbon atoms specified, or if no number is specified, having from four to eighteen carbon atoms, e
- “Fatty acid ester of a lower alkanol” refers to fatty acid esters wherein the alcohol group is a lower alkanol as defined above and the acid group is derived from fully saturated long chain fatty acids of eight to eighteen carbon atoms in length.
- Representative fatty acids include, for example caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, particularly the latter five named acids.
- the alcohol group could be derived from ethanol, isopropanol, n- propanol, t-butanol, n-butanol, isobutanol and the like.
- “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, and manganic salts, and the like.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine and other amines that are set forth in U.S. Patent 4,089,969, which is incorporated herein by reference in its entirety.
- Particularly preferred pharmaceutically acceptable salt is the tromethamine salt of ketorolac, i.e., ketorolac tromethamine.
- “Pharmaceutically acceptable ester” refers to an ester of ketorolac derived from an alkyl as defined above.
- Typical esters include, but are not limited to, ethyl, ethylpropyl, isopropyl, butyl,, t-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyl decyl, and dodecyl esters.
- Transdermally or “transdermal” refers to the passage of a drug into and through the skin layer (epidermis and dermis) of a subject to the subject's blood system.
- ketorolac is transdermally delivered to a subject in need thereof in order to achieve therapeutically effective blood levels of ketorolac in the subject.
- Transdermal delivery is to be distinguished from topical delivery which simply involves the penetration of the drug into the skin but not through it.
- topical administration of a drug will not involve the actual passage of the drug into the blood stream for systemic distribution.
- transdermal delivery of a therapeutically effective systemic amount of ketorolac to a subject in need thereof is achieved by maintaining a composition of the invention in relative contact with the skin of the subject for a time sufficient to allow a therapeutically effective amount of ketorolac contained therein to pass through the skin and to enter the bloodstream.
- “Therapeutically effective systemic amount” refers to that amount of ketorolac which, when transdermally administered to a subject in need thereof, is sufficient to cause the physiological response in the treatment of pain, inflammation and/or pyrexia in the subject.
- “Skin flux value” refers to the rate of an amount of drug, e.g. , ketorolac, transdermally delivered across an unit area of skin over a period of time.
- Biocompatible means that the aqueous vehicle of the invention does not have a significant adverse effect on the skin of the subject to which a device or composition of the invention is applied. In other words, the vehicle does not cause clinical irritation in the majority of subjects to . whom the device or composition is applied and it does not cause a subject's skin to slough or dissolve during and after administration.
- the amount of each ingredient used in the compositions is indicated herein as weight/weight percentages (% w/w) based on the weight of the ingredient and the total weight of the composition.
- This invention is to compositions and devices useful for transdermally delivering a therapeutically effective systemic amount of ketorolac to a subject in need thereof.
- compositions of this invention exhibit good in vi tro steady-state skin flux, which correlates to the amount absorbed in vivo, it is surprising that compositions of this invention show a rapid "onset of action" .
- the onset of action is the time between the application of the device or composition to a subject and the detection of the active entity in the blood stream.
- the active entity of ketorolac is detectable systemically within about 30 minutes to about 3 hours of the application of a device to the skin of a subject. This onset of action is much faster than would be predicted from the in vitro data and applying a well-established pharmacokinetic model of Guy and Hadgraft as explained in "The Prediction of Plasma Levels of Drugs Following Transdermal Application," J. Control .
- compositions and devices of this invention surprisingly show that therapeutic, systemic plasma levels of ketorolac can be achieved with a modest transdermal application area for the composition of only about 10 to 100 cm 2 , preferably about 20 to 50 cm 2 .
- the log of the diffusion coefficient is linearly related to the log of the molecular weight, with the slope of the line being dependent on the diffusion medium.
- the molecular weight of ketorolac is 255. This is between clonidine (230) and scopalamine (303), two compounds that are delivered transdermally in presently marketed products (Catapres TTS and Transderm-Scop, respectively) .
- the highest dose delivered per day from a 20 cm 2 transdermal patch of scopalamine is about 0.167 mg/day while the highest dose delivered of clonidine is about 0.3 mg/day. Extrapolating from this information, one would expect the highest dose of ketorolac delivered would be from about 0.2 to 0.3 mg/day.
- ketorolac has a melting point of 156°C. Two compounds that are delivered transdermally and have melting points close to ketorolac are estradiol (176°C) and clonidine (130°C) .
- the respective reciprocal melting points (1000/°K) for ketorolac, estradiol and clonidine are 2.33, 2.23 and 2.48. Extrapolating from this known information would result in an expected highest dose in mg/day similar to estradiol or clonidine, i . e . 1.0 or 0.3, respectively. Surprisingly the devices and compositions of this invention delivers about 30 to 120 mg/day or more.
- ketorolac whether as the acid, the salt or ester form, be soluble in the solvent mixture which is part of the composition and that the solution be saturated with ketorolac. Solid excess of ketorolac may be present in the composition to maintain a saturated condition of ketorolac in the solution and ensure that a therapeutically effective amount of ketorolac is delivered systemically.
- the therapeutic systemic effective amount of ketorolac in the blood of the subject being treated using a device of this invention will be about 0.1 micrograms ( ⁇ g) of ketorolac per milliliter (mL) of blood to about 4.0 ⁇ g ketorolac per milliliter (mL) of blood.
- the device of this invention administers ketorolac at a rate of about 0.2 milligrams (mg) per hour to about 4.0 mg per hour to a 70 kilogram (Kg) person.
- the device of this invention is designed to deliver ketorclac for up to four days at a substantially constant rate, i.e., the device has a delivery life of up to about four days.
- the device of this invention is particularly valuable for managing short term pain, e. g. , post-operative pain.
- the device will be used in conjunction with an injection of ketorolac into a subject in need thereof so that the subject has immediate relief from the pain and sustained relief of the pain over the delivery life of the device.
- the necessary blood levels needed by the subject could be obtained by administering ketorolac orally and using the device to deliver ketorolac for a sustained period of time.
- compositions of this invention comprise ketorolac dissolved in a biocompatible aqueous vehicle wherein the composition exhibits a skin flux value sufficient to deliver a systemic amount of ketorolac to a subject's blood stream.
- ketorolac is present in an amount sufficient to form a saturated solution.
- the vehicle that is used as part of the composition of this invention is biocompatible and allows the ketorolac to pass through the skin at a substantially constant rate through the delivery life of the composition.
- the composition must be designed so that the ketorolac is released from the composition as contained in the device (described hereinafter) through the membrane and to the skin at a substcintially constant rate.
- the composition exhibits a pH of about 3 to about 8 and the composition will retain such a pH range throughout the delivery life of the device.
- the pH may be adjusted during preparation of the composition to the appropriate range by adjusting with an acid or base depending on the ketorolac source used. If necessary, a buffer system, such as those employing citrate or phosphate entities, may be used to adjust and maintain the pH. If, as in a preferred mode, ketorolac is present in the composition as ketorolac tromethamine, the pH is adjusted using hydrochloric acid (about 1 Normal [N] ) . Preferably, the pH of the composition will be about 4.0 to about 6.0.
- the vehicle will, as a minimum, contain water and a lower alkanol.
- the lower alkanols used in the invention are physiologically acceptable in that they are biocompatible with the skin and aid in the stability of the ketorolac particularly if ketorolac is present as an ester with two, three or four carbon atoms when preparing the composition.
- ethanol and isopropanol are preferred, particularly isopropanol.
- the vehicle preferably also contains a fatty ester of a lower alkanol.
- the lower alkanol are physiologically acceptable in that they are biocompatible with the skin.
- the vehicle will contain the ester of the physiologically acceptable lower alkanol present in the vehicle.
- the fatty ester of a lower alkanol used in the invention is i ⁇ opropyl myristate.
- Other pharmaceutically acceptable excipients may be included in the compositions of this invention to improve the stability, compatibility, appearance, or other characteristics of the composition.
- small amounts of solvents, scavengers or preservatives such as antioxidants
- Representative antioxidants include butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) .
- Edetate disodium may be used also.
- the composition comprises: (a) from about 20% w/w to about 80% w/w water; (b) from about 20% w/w to about 80% w/w lower alkanol;
- the composition comprises:
- the composition comprises:
- the composition comprises:
- ketorolac a composition of the invention which further comprises a gelling agent in an amount sufficient to gel the composition.
- This composition allows the dissolved ketorolac to pass through the skin at a substantially constant rate over the delivery life of a device which contains the composition.
- the gelling agent useful in the compositions of this invention must be compatible with ketorolac (i.e., be non-reactive with ketorolac), compatible with the vehicle, and bio-compatible with the subject's skin. While numerous gelling agents are available for this purpose, we have found that polyhydric derivatives of cellulose are particularly valuable.
- Examples include carboxymethylcelluloses; hydroxyalkylcelluloses (such as hydroxypropylcellulose) ; carboxyvinyl polymers having a molecular weight of approximately from 1,250,000 to 4,000,000, e . g. , carbomer 934, carbomer 940, and carbomer 941; carboxyvinyl polymer derivatives having the tradename CARBOPOL ® 1342 and the like; cellulose derivatives having the tradenames KLUCEL ® HF and NATROSOL PLUS ® and the like. Particularly useful in the compositions of the invention is hydroxypropylcellulose and carbomer 940.
- the gelling agent will be present at a level of about 0.5% w/w to about 10.0% w/w of the composition, preferably about 1.0% w/w to about 5.0% w/w.
- a saturated solution of ketorolac is prepared by first preparing the biocompatible aqueous vehicle having the appropriate ratio of ingredients and adding ketorolac to the vehicle generally at a temperature range of from 23°C to 30°C, usually ambient temperature, while stirring until no more material dissolves. A slight excess of ketorolac is added to maintain a saturated solution. The pH is adjusted as needed and the gelling agent is added, if desired, until the desired gelled composition is obtained.
- gelled it is meant the unique type of rheological behavior which exhibits a viscosity of about 5,000 cps to 40,000 cps as measured by a standard viscometer.
- the composition is then ready for use in preparing a device, of this invention.
- a device of this invention contains about 500 mg to about to 10.0 grams of the composition in order to deliver the systemic amount of ketorolac desired.
- FIG. 1 a preferred embodiment of a device of the invention for transdermally delivering a therapeutically effective systemic amount of ketorolac in accordance with this invention is shown.
- the device comprises (a) a composition (1) of the invention as described above; (b) a reservoir (2) for containing the composition, wherein the reservoir is defined by an impermeable backing (3) and a membrane (4) to retain the composition within the reservoir and to allow for the release of ketorolac through the membrane; and (c) means (5) to maintain the side of the device opposite the backing in contact with the skin of the subject to allow the transdermal administration of ketorolac.
- the device may optionally include (d) a release liner (6) to protect the device during storage.
- Figure 2 A the device of Figure 1 is viewed from a top view showing a circular device. It will be recognized by one skilled in the art that the shape of the device from this view may be square, rectangular, oblong, or other appropriate shape.
- the device of Figure 1 without the optional release liner is viewed from the bottom showing the outer perimeter of means (5) to maintain the side of the device opposite the backing (3) (i.e., the membrane side) in contact with the skin of the subject, and the membrane (4) .
- Figure 3 depicts another embodiment of a device of this invention, wherein the means (5) for maintaining the side opposite the backing (3) (i.e., the membrane side) is spread across the entire membrane (4) .
- the impermeable backing (3) that defines the reservoir in the devices of this invention may be of any material suitable for such backing which is known in the art. Examples of such material are set forth in various patents such as U.S. Patent No ⁇ . 3,598,122; 4,144,317; 4,201,211; 4,262,003; and 4,379,454; all of which are incorporated herein by reference as representative of various transdermal drug delivery devices of the prior art which show backing systems useful for this invention. While this invention contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known in the art and are capable of performing the necessary function of providing the impermeable backing material, the material which is taught in this application are particularly useful.
- impermeable backing useful in this invention include polyester backing; polypropylene backing; high and low density polyethylene.
- the thickness of the backing is about 1 mil (1/1000 of an inch) to about 5 mil.
- the membrane material useful for this device may include materials such ethylene vinyl acetate (EVA) , or porous polyethylene or polypropylene having pores of about 1 to about 5 microns.
- EVA ethylene vinyl acetate
- a useful example is 3M COTRAN ® material, which is an extruded ethylene vinyl acetate film produced by 3M Health Care Group.
- the membrane material is generally attached to the impermeable backing by means known in the art such as heat sealing as generally taught in Remington's discussion of preparing blister packs.
- the membrane used in the devices of this invention will be of a size sufficient to allow for the composition of the invention to be transdermally delivered on an area of the subject's skin from about 10 cm 2 to about 100 cm 2 , preferably from about 20 cm 2 to about 50 cm 2 .
- the means to maintain the side of the device opposite the backing in contact with the skin of the subject is generally an adhesive chosen from the type of adhesives known in the art for this purpose.
- adhesives include medical grade adhesives such as silicone-based adhesives available from Dow-Corning Corporation. Representative examples include polyisobutylene (from Exxon Corporation or Amoco Corporation) ; and acrylate adhesives (such as Monsanto's Gelva 737, Gelva 788 or mixtures thereof) . Others may be readily apparent to those of skill in the art.
- the thickness of the adhesive layer may vary between about one mil to about five mils, but in any event is sufficient to maintain contact of the device to the subject's skin.
- the adhesive is attached to the periphery of the device as shown- in Figure 1. This generally allows for a more rapid onset of action. Alternatively, the adhesive may be spread across the entire membrane as shown in Figure 3. If this configuration is employed, the onset is not as rapid because it delays the diffusion of ketorolac.
- the optional release liner that is used to protect the device during storage and to prevent the premature release of ketorolac may be any appropriate medical grade release liner compatible with the means, membrane and device generally.
- Such liners may be polyester or other suitable polymeric material.
- a liner of particular value is 3M 1022 that has a silicone-treated surface that contacts the adhesive for easy release.
- This example sets forth the solubility of ketorolac in mixtures of water and a physiologically acceptable lower alkanol, isopropanol (IPA) :
- ketorolac The solubility of ketorolac in each mixture is set forth in Table I: Table I
- ketorolac is determined using other vehicle mixtures such as ethanol/water, n-propanol/water, t-butanol/water, n- butanol/water, and the like.
- This example sets forth the solubility of ketorolac in the biocompatible aqueous vehicles of the invention:
- solubility of other forms of ketorolac in the compositions of the invention is determined using other vehicles such as ethanol/water/ethyl myristate, n-propanol/water/n-propyl laurate, t -butanol/water/ 1-butylcarprylate, n-butanol/water/n-butyl myristate, and the like.
- This example describes experiments that were run to compare the in vitro skin flux of compositions of this invention to the skin flux of certain related compositions.
- the Diffusion Cell System An automated flow-through diffusion cell system was designed for use in the in vitro transdermal screening studies. The system automatically sampled from up to twelve flow-through diffusion cells while simultaneously drawing fresh receptor phase into the cell. Samples were analyzed by HPLC and raw chromatography data were collected in a data acquisition interface. The data was then uploaded onto an IBM PC AT and stored, processed and/or linked to other scientific software to provide the results.
- the diffusion cells used in this system were flow-through Franz-type diffusion cells from the Crown Glass Company (#FCS-200 Flow-Thru Diffusion Cells) .
- the large cell orifice diameter (20 mm) accommodated human cadaver skin, which was obtained from Northern California Transplant Bank as freshly dermatomed, upper thigh skin 0.012" thick, stored in a refrigerated buffer solution of saline, glucose and vitamins (Eagles medium) .
- Gentamacin sulfate was added to the skin to prevent bacterial growth.
- These cells were jacketed at temperatures of about 37°C using a bath circulator (Neslab Instruments Model #RTE-9) .
- Receptor phase recirculation in the diffusion cell receptor chambers was accomplished using a low flow, multichannel, cartridge peristaltic pump (Cole-Parmer Instruments #7618- 60) .
- Sampling, analysis and data collection were controlled by a programmable controller (Minarik Electric MicroMaster Controller #WP 6201 and Input/Output Expander #WP 6301) .
- Eight output channels were connected to the sampling valve, one output was connected to the injection valve, one output was connected to the integrator and one output was connected to the data acquisition interface.
- Samples from the diffusion cells were analyzed by UV detection following automatic injection onto an HPLC column (mobile phase: 44/58/1 CH 3 CN/H 2 ⁇ /CH 3 COOH) .
- Data were collected by a standard liquid chromatography integrator (IBM LC/9540) or by a data acquisition interface (Nelson Analytical Series 3000 Model 2600 Chromatography Data System) which is programmed through an IBM PC AT. The Nelson Analytical Series 3000 chromatography Data System was used to acquire and monitor the results.
- Solubility measurements were performed on the volume remaining after the 20 mL composition from Part A above was used in the diffusion cell system of Part B above. Samples were shaken for 5 minutes and allowed to sit 3 to 5 days at room temperature, protected from light. Three mL samples of solution were filtered through 0.2 ⁇ Acrodi ⁇ c filters. Samples of 0.5 mL were withdrawn and diluted with mobile phase to 250 mL. Diluted samples were assayed using HPLC method listed above. (Samples were not shaken prior to filtering because several formulations formed non- filterable emulsions after mixing, resulting in much higher drug content compared to solutions sitting at equilibrium) . D. Results.
- IPA isopropanol
- IPM isopropyl myristate
- This example sets forth a repre ⁇ entative compo ⁇ ition of this invention comprising a saturated solution of ketorolac, isopropanol (IPA) , water and isopropyl myri ⁇ tate (IPM) .
- ketorolac A ⁇ aturated solution of ketorolac was prepared by dissolving ketorolac in the following vehicle mixture: IPA 57.9% w/w IPM 5.3% w/w water 36.8 w/w The saturated solution contained 69.5 mg/mL of ketorolac.
- the receiver fluid wa ⁇ ⁇ tirred throughout the experiment.
- the ⁇ kins were allowed to equilibrate with buffer solution for 30 minute ⁇ .
- the receiver ⁇ ample ⁇ were injected into HPLC before charging the donor solution to ensure the absence of interfering peaks from the skin and receiver fluid.
- the donor compartment wa ⁇ then changed respectively with 3 mL of the above solution.
- the donor compartment was occluded immediately with plastic wrap to prevent any significant los ⁇ of volatile components from the solution.
- the receiver fluids were sampled over a period of 28 hours at 3 hour time intervals.
- the concentration of ketorolac acid or tromethamine salt in the receiver compartment of the diffu ⁇ ion cell was assayed by HPLC.
- the amount ( ⁇ g/cm 2 ) of ketorolac permeated through split-thickne ⁇ ⁇ kin wa ⁇ plotted against time (0 to 28 hours) , and the mean skin flux ( ⁇ g/cm 2 /h) was determined from the slope of the cumulative amount/time plot after the attainment of psuedo-steady state.
- Both placebo and active Hill Top Chambers were removed at 24 hours and the two sites were evaluated for skin irritation. The sites were scored on the scale of 0 to 4 with an increment of 1 from no irritation to severe irritation caused by the placebo or active transdermal solutions.
- the used active Hill Top Chambers were collected and as ⁇ ayed for residual ketorolac acid content in the patches. Briefly, the drug was extracted from the Hill Top Chamber simply by placing the chamber in a beaker containing 50 mL of HPLC mobile phase (see below for the composition) . The solution was then sonicated for 5 minutes to release the drug into the mobile phase. One mL of solution was withdrawn from the beaker and tran ⁇ ferred into a HPLC vial.
- the formulation showed mild to moderate skin irritation in some subjects. Surprisingly, detectable drug levels in plasma were ⁇ een within an hour of application. The average amount of ketorolac ab ⁇ orbed in 24 hours in the ⁇ ubject ⁇ u ⁇ ing the Wagner-Nelson method was 31.2 mg.
- Example 2 The compositions of Example 2 are gelled by adding 1.1% w/w KLUCEL ® brand hydroxypropyl cellulose.
- Transdermal Device Peripheral Adhesive Mean ⁇
- a compo ⁇ ition of Example 5 i ⁇ prepared to provide a 6.5% ketorolac tromethamine in a biocompatible aqueous gelled vehicle mixture comprising isopropanol, water and isopropyl myristate (50:50:1.4).
- a 10 cm 2 liquid- reservoir type transdermal device of the invention is prepared by placing 0.9 g of the gelled composition on a polyester/polyethylene composite film as the impermeable backing material followed by heat-sealing a microporous membrane (3M CoTran ® 9710) as a non-rate controlling membrane along the periphery of the backing material.
- a microporous membrane 3M CoTran ® 9710
- the device is applied to skin by means of pressure sensitive adhesive (PSA) along the periphery of the device.
- PSA pressure sensitive adhesive
- Figure 1 shows ⁇ the approximate cross-section of this liquid-reservoir tran ⁇ dermal device.
- a 20 cm 2 liquid reservoir transdermal device of the invention is prepared by placing 1.5 g of the composition of Example 5 on to metallized polyester/Surlyn 1652 (Schupbach) membrane as a backing film followed by immediate heat-sealing of a microporous membrane (3M CoTran ® 9710) containing continuous adhesive layer act as a contact adhesive.
- Two types of pressure sensitive contact adhesives may be used on the device: a) amine-resistant silicone adhesive (Bio-PSA ® X7-4301, Dow Corning) ; b) polyacrylic copolymer (MA-31) .
- the thickness of adhesive layer may vary from 1 to 4 mil.
- a polyester release liner (3M 1022 or ARMS liner) is used to protect the adhesive layer from adhering to undesirable surface ⁇ .
- Figure 3 shows the cross-section of this device. The release liner is removed from the device, which may then be applied immediately to the skin with a slight pressure. The skin permeation experiments are conducted as described in Example 3. The following values were obtained:
- a 10 cm 2 liquid reservoir transdermal device is prepared by placing 1 g of the composition of Example 6 on to metallized polyester/Surlyn 1652 (Schupbach) membrane as the impermeable backing material, followed by immediate heat-sealing an ethylene vinyl acetate (EVA) membrane as a rate controlling membrane.
- EVA ethylene vinyl acetate
- the composition of vinyl acetate in the EVA membrane may vary from 4.5 to 40% to modulate the delivery of both drug and vehicle.
- Figure 1 ⁇ hows the cros ⁇ - ⁇ ection of thi ⁇ device.
- Cadaver skin ( ⁇ 300 ⁇ m thickness) was used for the skin permeation studies using modified Franz static diffusion cells.
- the skin was mounted carefully on a Franz diffusion cell and fastened with an O-ring.
- the receiver fluid was stirred throughout the experiment.
- the skins were allowed to equilibrate with buffer solution for 30 min.
- the receiver fluid (1 mL) was withdrawn and injected into an HPLC before charging the donor solution to ensure the absence of any interfering peak ⁇ from the ⁇ kin tissue ⁇ .
- the donor compartment was then charged with the drug solution and the sampling port was closed with a rubber stopper to prevent any ⁇ ignificant lo ⁇ s of volatile components from the solution.
- 1 mL of receiver fluid was withdrawn from the receiver compartment and replaced with fresh receiver fluid. The samples were then as ⁇ ayed by HPLC.
- ketorolac acid was as ⁇ ayed by HPLC using a chiral column (Chiral AGP (100 x 4.6 mm), mobile phase: 40-60 mM phosphate buffer) . Racemic ketorolac acid was also assayed by the same method where both R- and S-isomers were independently quantitated. No apparent interconversion of one isomer to another isomer during the entire period of analysi ⁇ and diffu ⁇ ion experiment ⁇ was ob ⁇ erved. D. Data Analysis.
- EXAMPLE 10 A gelled composition of this invention suitable for preparing a transdermal device is prepared as follows:
- the composition was prepared by first mixing the isopropanol and the isopropyl myristate. Ketorolac tromethamine in the necessary amount of• water was then added to the isopropanol/isopropyl myristate mixture at room temperature while stirring until no more solid material dissolve. The pH was adjusted as needed with IN HC1. The gelling agent, KLUCEL ® HF, was slowly added to the composition until the desired viscosity was achieved.
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Abstract
Cette invention se rapporte à une composition permettant d'administrer par voie transdermique une dose thérapeutique efficace de kétorolac à un sujet nécessitant ce médicament; la composition comprenant du kétorolac dissous dans un excipient aqueux biocompatible, et présentant une valeur de flux cutané suffisante pour apporter une dose systémique de kétorolac dans le flux sanguin du sujet. Cette invention se rapporte également à des dispositifs destinés à l'apport transdermique de ces compositions, ainsi qu'à des procédés permettant d'administrer par voie transdermique une dose systémique et thérapeutique efficace de kétorolac à des sujets nécessitant un tel traitement.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU54504/94A AU5450494A (en) | 1992-10-30 | 1993-10-29 | Transdermal delivery of ketorolac |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US96880092A | 1992-10-30 | 1992-10-30 | |
US07/968,800 | 1992-10-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994009777A1 true WO1994009777A1 (fr) | 1994-05-11 |
Family
ID=25514795
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/010219 WO1994009777A1 (fr) | 1992-10-30 | 1993-10-29 | Apport transdermique de ketorolac |
Country Status (5)
Country | Link |
---|---|
AU (1) | AU5450494A (fr) |
IL (1) | IL107448A0 (fr) |
MX (1) | MX9306791A (fr) |
WO (1) | WO1994009777A1 (fr) |
ZA (1) | ZA938116B (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2414675A (en) * | 2004-06-05 | 2005-12-07 | Dewan Fazlul Hoque Chowdhury | Transdermal Drug Delivery Device |
DE102007034976A1 (de) | 2007-07-26 | 2009-01-29 | Bayer Healthcare Ag | Arzneimittel zur transdermalen Anwendung bei Tieren |
US8758311B2 (en) | 2009-02-02 | 2014-06-24 | Nemaura Pharma Limited | Transdermal patch with extensor means |
WO2017095730A1 (fr) * | 2015-11-30 | 2017-06-08 | Elliptical Therapeutics, Llc | Systèmes et méthodes pour l'administration transdermique de médicament |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4454151A (en) * | 1982-03-22 | 1984-06-12 | Syntex (U.S.A.) Inc. | Use of pyrrolo pyrroles in treatment of ophthalmic diseases |
JPH0372433A (ja) * | 1989-04-28 | 1991-03-27 | Hisamitsu Pharmaceut Co Inc | 泡状エアゾール製剤 |
US5091182A (en) * | 1990-07-23 | 1992-02-25 | Syntex (U.S.A.) Inc. | Dispensing units for ketorolac topical gel formlations |
JPH0499719A (ja) * | 1990-08-20 | 1992-03-31 | Riide Chem Kk | 外用貼付剤 |
JPH04321624A (ja) * | 1991-04-19 | 1992-11-11 | Hisamitsu Pharmaceut Co Inc | 消炎鎮痛貼付剤 |
-
1993
- 1993-10-29 IL IL107448A patent/IL107448A0/xx unknown
- 1993-10-29 MX MX9306791A patent/MX9306791A/es unknown
- 1993-10-29 WO PCT/US1993/010219 patent/WO1994009777A1/fr active Application Filing
- 1993-10-29 ZA ZA938116A patent/ZA938116B/xx unknown
- 1993-10-29 AU AU54504/94A patent/AU5450494A/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4454151A (en) * | 1982-03-22 | 1984-06-12 | Syntex (U.S.A.) Inc. | Use of pyrrolo pyrroles in treatment of ophthalmic diseases |
JPH0372433A (ja) * | 1989-04-28 | 1991-03-27 | Hisamitsu Pharmaceut Co Inc | 泡状エアゾール製剤 |
US5091182A (en) * | 1990-07-23 | 1992-02-25 | Syntex (U.S.A.) Inc. | Dispensing units for ketorolac topical gel formlations |
JPH0499719A (ja) * | 1990-08-20 | 1992-03-31 | Riide Chem Kk | 外用貼付剤 |
JPH04321624A (ja) * | 1991-04-19 | 1992-11-11 | Hisamitsu Pharmaceut Co Inc | 消炎鎮痛貼付剤 |
Non-Patent Citations (5)
Title |
---|
CHEMICAL ABSTRACTS, vol. 109, no. 16, 17 October 1988, Columbus, Ohio, US; abstract no. 134901x * |
CHEMICAL ABSTRACTS, vol. 115, no. 16, 21 October 1991, Columbus, Ohio, US; abstract no. 166660h * |
CHEMICAL ABSTRACTS, vol. 118, no. 18, 3 May 1993, Columbus, Ohio, US; abstract no. 175803w * |
DATABASE WPI Week 9219, Derwent World Patents Index; AN 92-157308 (19) * |
DIANA YU ET AL.: "PERCUTANEOUS ABSORPTION OF NICARDIPINE AND KETOROLAC IN RHESUS MONKEYS", PHARM. RES., vol. 5, no. 7, 1988, pages 457 - 462 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2414675A (en) * | 2004-06-05 | 2005-12-07 | Dewan Fazlul Hoque Chowdhury | Transdermal Drug Delivery Device |
GB2414675B (en) * | 2004-06-05 | 2006-09-06 | Dewan Fazlul Hoque Chowdhury | Transdermal drug delivery device |
DE102007034976A1 (de) | 2007-07-26 | 2009-01-29 | Bayer Healthcare Ag | Arzneimittel zur transdermalen Anwendung bei Tieren |
US8758311B2 (en) | 2009-02-02 | 2014-06-24 | Nemaura Pharma Limited | Transdermal patch with extensor means |
WO2017095730A1 (fr) * | 2015-11-30 | 2017-06-08 | Elliptical Therapeutics, Llc | Systèmes et méthodes pour l'administration transdermique de médicament |
CN108289859A (zh) * | 2015-11-30 | 2018-07-17 | 椭圆疗法有限公司 | 用于透皮给药的系统和方法 |
Also Published As
Publication number | Publication date |
---|---|
MX9306791A (es) | 1995-01-31 |
IL107448A0 (en) | 1994-01-25 |
ZA938116B (en) | 1995-05-02 |
AU5450494A (en) | 1994-05-24 |
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