United States Patent [19]
`Ong et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`USOO5091182A
`[II] Patent Number:
`[45] Date of Patent:
`
`5,091,182
`Feb. 25, 1992
`
`[75]
`
`[54] DISPENSING UNITS FOR KETOROLAC
`TOPICAL GEL FORMLATIONS
`Inventors: John T. H. Ong, Palo Alto; Jean S.
`Fujiki, Sunnyvale; Wei-Cheng Liaw,
`Redwood City, all of Calif.
`[73] Assignee: Syntex (U.S.A.) Inc., Palo Alto, Calif.
`[21] Appl. No.: 556,938
`Jul. 23, 1990
`[22] Filed:
`Int. Cl.s .............................................. A61K 09/00
`[51]
`[52] U.S. Cl' .................................... 424/400; 514/817;
`514/886; 514/887; 514/944; 514/947
`[58] Field of Search ....................... 424/401,427,428;
`514/886, 887, 969, 944, 817,947
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`4,089,969 5/1978 Muchowski et aJ. ............... 514/416
`4,418,841 12/1983 Eckstein ............................... 222/107
`4,454,151 6/1984 Waterbury .......................... 514/413
`4,540,572 9/1985 Seth ....................................... 424/81
`
`4,551,371 11/1985 Eckstein ................................ 428/36
`4,568,000 211986 Middleton ........................... 222/707
`4,659,408 4/1987 Redding .............................. 428/461
`4,764,361 8/1988 Bilski et aI ............................ 424/45
`4,871,767 10/1989 Beckermann et aI ............... 514/536
`4,919,939 4/1990 Baker .................................. 424/493
`4,943,780 7/1990 Redding ............................. 428/35.9
`4,946,787 8/1990 Eppstein et aI .................. 435/240.2
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-Robert H. Harrison
`Attorney, Agent, or Firm-Carol J. Roth; Derek P.
`Freyberg; Tom M. Moran
`
`[57]
`ABSTRACT
`A dispensing unit for a ketorolac topical gel formulation
`is disclosed, wherein the dispensing unit comprises a
`ketorolac topical gel formulation and a gas-impermea(cid:173)
`ble multi-layered container wherein the container is
`comprised of a polyolefin inner layer and a metal foil
`outer layer.
`
`12 Claims, No Drawings
`
`L'OREAL USA, INC. EX. 1007
`
`1 of 5
`
`

`

`1
`
`5,091,182
`
`BACKGROUND OF THE INVENTION
`This invention relates to dispensing units for ketoro(cid:173)
`lac topical gel formulations which are comprised of the
`gel formulation in a gas-impermeable multi-layered
`container.
`Ketorolac and its pharmaceutically acceptable salts 10
`are known to be effective in treating inflammation and
`pain in mammals. See, e.g., U.S. Pat. No. 4,089,969 and
`U.S. Pat. No. 4,454,151. Dispensing units for ketorolac
`topical gel formulations require specific packaging
`specifications in order to maintain chemical stability of 15
`the formulation and physical integrity of the container.
`For example, the use of containers which are con(cid:173)
`structed of only polyolefins for dispensing units for
`ketorolac topical gel formulation results in undesirable
`changes in the formulation due to solvent evaporation. 20
`We have discovered that a dispensing unit for ketorolac
`topical gel formulations which is comprised of a con(cid:173)
`tainer constructed of a polyolefin inner layer and a
`metal foil outer layer will maintain the chemical stabil-
`ity of the formulation contained within while at the 25
`same time the physical integrity of the container is
`maintained.
`
`2
`atoms and that is substituted by one hydroxy group,
`e.g., methanol, ethanol, isopropyl alcohol, n-butanol, or
`t-butyl alcohol.
`The term "penetration enhancer" refers to a com-
`5 pound that enhances the penetration through the skin of
`the active ingredient(s) of a formulation in which the
`penetration enhancer is contained, e.g., ethanol, propy(cid:173)
`lene glycol, pyrrolidones, dimethyl sulfoxide, dimethyl-
`acetamide,. dimethylformamide, I-dodecylazacyclohep(cid:173)
`tan-2-one (Azone ®) decylmethyl sulfoxide, oleic acid
`or diisopropyl adipate. A typical effective amount of a
`penetration enhancer in a ketorolac topical gel formula(cid:173)
`tion is between about 0.5% and 5.0% w/w.
`The term "chelating agent" refers to a compound
`that complexes metal ions which catalyze the degrada(cid:173)
`tion of the active ingredient(s) ofa formulation in which
`the chelating agent is contained, e.g., ethylenediamine- .
`tetraacetic acid (EDT A), citric acid, dihydroxyethyl
`glycine, tartaric acid, tryptophan, and their pharmaceu-
`tically acceptable salts, e.g., EDT A disodium salt. An
`effective amount of a chelating agent in a ketorolac
`topical gel formulation is between about 0.001 % and
`0.1% w/w.
`The term "antioxidant" refers to a compound that
`retards deterioration by oxidation of the active in(cid:173)
`gredient(s) of a formulation in which the antioxidant is
`contained, e.g., sodium bisulfite, ascorbic acid, butyl(cid:173)
`ated hydroxy toluene (BHT) or butylated hydrox-
`SUMMARY OF THE INVENTION
`This invention is a dispensing unit for a ketorolac 30 yanisole (BHA). An effective amount of an antioxidant
`topical gel formulation, wherein the dispensing unit
`of a ketorolac topical gel formulation is between about
`0.001% and 0.1% w/w.
`comprises:
`(a) a ketorolac topical gel formulation comprising:
`The term "thickening agent" refers to a compound
`(i) ketorolac, or a pharmaceutically acceptable salt
`that, when added to a liquid or solution, produces a gel.
`thereof, in an amount between 0.1 % and 5.0% 35 Examples of thickening agents for aqueous or aqueous-
`w/w;
`/alcoholic solutions are carboxymethyl cell uloses; hy-
`(ii) a lower alkanol in an amount between 30% and
`droxyalkylcelluloses, e.g., hydroxymethylcellulose and
`45% w/w;
`hydroxypropylcellulose; carboxyvinyl polymers having
`(iii) a thickening agent in an amount sufficient to gel
`a molecular weight of approximately from 1,250,000 to
`40 4,000,000, e.g, carbomer 934, carbomer 940, and car-
`said formulation; and
`(iv) water q.s. to 100%; and
`bomer 941; and polyoxypropylene-polyoxyethylene
`block polymers, e.g., Pluronic ® F127. Carbomers are
`(b) a gas-impermeable multi-layered container contain-
`ing said formulation, which container comprises:
`synthetic high molecular weight polymers of acrylic
`(i) an inner layer in direct contact with said formula-
`acid cross-linked with allyl ethers of sucrose or penta-
`tion, which inner layer comprises a polyolefm; and 45 erythritol. Pluronics ® are polyoxypropylene-polyox-
`yethylene block polymer available from BASF-Wyan(cid:173)
`(ii) an outer layer comprising a metal foil.
`dotte. Pluronics ® are identified by a letter prefix fol(cid:173)
`lowed by a two or a three digit number. The letter
`prefixes L, P and F refer to the physical form of each
`SO polymer, i.e., L-liquid, P-paste, and F-flakeable solid.
`The two and three digit numbers are used to designate
`the average molecular weight of the polyoxypropylene
`hydrophobic midsection of the block polymer in com(cid:173)
`parison with the percent polyoxyethylene in the total
`55 molecule.
`The term "pharmaceutically acceptable salt" refers to
`those salts which retain the biological effectiveness and
`properties of the free bases and which are not biologi(cid:173)
`cally or otherwise undesirable. These salts are prepared
`from either inorganic or organic bases. Salts derived
`from inorganic bases include, but are not limited to, the
`sodium, potassium, lithium, ammonium, calcium, mag(cid:173)
`nesium, ferrous, zinc, copper, manganous, aluminum,
`ferric, manganic salts, and the like. Preferred inorganic
`salts are the ammonium, sodium, potassium, calcium,
`and magnesium salts. Salts derived from organic bases
`include, but are not limited to, salts of primary, second(cid:173)
`ary, and tertiary amines, substituted amines including
`
`DISPENSING UNITS FOR KETOROLAC TOPICAL
`GEL FORMLATIOl"OS
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`Defmitions
`As used in this specification, unless specified to the
`contrary, the following terms have the meaning indi(cid:173)
`cated:
`"Ketorolac" is (± )-5-benzoyl-2,3-dihydro-l H-pyr(cid:173)
`rolizine-l-carboxylic acid (USAN).
`The term "polyolefin" refers to a thermoplastic poly(cid:173)
`mer derived from olefms by bomopolymerization, e.g.,
`polyethylene (such as low density polyethylene), poly(cid:173)
`propylene, polybutylene, and the like; or by copolymer(cid:173)
`ization of an olefm with at least one other olefmically 60
`unsaturated monomer, such as another olefm, giving
`copolymers such as ethylene-propylene copolymers, or
`monomers containing vinyl esters or acrylic acid or
`ester groups giving copolymers such as ethylene/acry-
`lic acid copolymer (EAA), ethylene/vinyl acetate co- 6S
`polymer (EVA), and the like.
`The term "lower alkanol" refers to a saturated ali(cid:173)
`phatic hydrocarbon that has from one to six carbon
`
`2 of 5
`
`

`

`5,091,182
`
`10
`
`3
`naturally-occurring substituted amines, and cyclic
`amines, including isopropylamine, trimethylamine, di(cid:173)
`ethylamine,
`triethylamine,
`tripropylamine. ethanol(cid:173)
`amine, 2-dimethylaminoethanol, tromethamine, lysine,
`arginine, histidine, caffeine, procaine, hydrabamine, 5
`choline, betaine, ethylenediamine, glucosamine, N(cid:173)
`aIkylglucamines, theobromine, purines, piperazine, pi(cid:173)
`peridine, N-ethylpiperidine, and the like. Preferred or(cid:173)
`ganic bases are isopropyl amine, diethylamine, ethanol-
`amine, piperidine, tromethamine, and choline.
`The term "pH control agent" refers to those organic
`and inorganic bases and acids which may be added to a
`formulation of the invention in order to maintain the pH
`of the formulation within a certain range. For example,
`tromethamine may be added to a formulation in order to 15
`raise the pH; hydrochloric acid, in order to lower it. A
`desirable pH for a formulation of the invention is from
`about 3.8 to about 4.6, preferably at about 4.2.
`The ketorolac topical gel formulations contained
`within the dispensing units of the invention are gener- 20
`aIJy prepared by first dissolving ketorolac, or a pharma(cid:173)
`ceuticaIJy acceptable salt thereof, and a chelating agent
`in purified water to form an aqueous solution. If neces(cid:173)
`sary, a pH control agent, preferably tromethamine, is 25
`then added to the aqueous solution in order to maintain
`the desired pH of the formulation. In a separate vessel,
`a lower alkanol, preferably isopropyl alcohol; a penetra(cid:173)
`tion enhancer, preferably diisopropyl adipate; and an
`antioxidant, preferably BHT, are then mixed together to 30
`form an alcoholic solution. A thickening agent, prefera(cid:173)
`bly a carboxyvinyl polymer, e.g., carbomer 940, is then
`evenly dispersed into this alcoholic solution. The aque(cid:173)
`ous solution containing ketorolac, or a pharmaceuti(cid:173)
`cally acceptable salt thereof, is then added to the alco- 35
`holic solution and the resulting mixture is slowly stirred
`until gelling is complete.
`The gas-impermeable multi-layered containers of the
`dispensing units are constructed of a material comprised
`of consecutive layers which are firmly adhered to each 40
`other to make a unitary structure. Examples of such
`material are described in U.S. Pat. No. 4,659,408 (Amer(cid:173)
`ican Can Company) and U.S. Pat. No. 4,418,841 (Amer(cid:173)
`ican Can Company). The consecutive layers of the
`containers are positioned such that only one layer is in 45
`direct continuous contact with the formulation con(cid:173)
`tained within. The term "inner layer" therefore refers to
`that layer of the container which is in direct contact
`with the formulation contained therein. Such inner
`layers are comprised of a polyolefm, as defined above. 50
`The term "outer layer" refers to a layer of the con(cid:173)
`tainer which is outside of the inner layer, as described
`above. Such outer layer is comprised of a metal foil
`which prevents the passage of gases or vapors to and
`from the contained formulation. The outer layer need SS
`not be in direct contact with, or adjacent to, the inner
`layer, i.e., another layer or other layers may be between
`the inner layer and the outer layer. Such outer layer also
`need not be the outermost layer of the container, i.e.,
`another layer or other layers may be outside the outer 60
`layer. Layers other than the inner layer and the outer
`layer may be comprised of polyolefins or paper.
`The containers, as described above, may be in various
`shapes and forms, including, but not limited to, tubes
`and pouches. It is preferred that such containers are 6S
`capable of being deformed or collapsed by external
`pressure in order to extrude a formulation contained
`therein.
`
`4
`The dispensing units of the invention are therefore
`prepared by filling by conventional methods known to
`those skilled in the art a gas-impermeable multi-layered
`container, as described above, with a ketorolac topical
`gel formulation, as prepared above. The resulting dis(cid:173)
`pensing unit may then be used to topicalJy administer an
`amount of the formulation contained therein to an ani(cid:173)
`mal, preferably a human, in need thereof.
`
`PREFERRED EMBODIMENTS
`Dispensing units of the invention are comprised of a
`ketorolac topical gel formulation, which is comprised of
`ketorolac, or a pharmaceutically acceptable salt thereof,
`in an amount between 0.1% and 5.0% w/w; a lower
`alkanol in an amount between 30% and 45% w/w; a
`thickening agent in an amount sufficient to gel the for(cid:173)
`mulation; and water q.s. to 100%; and a gas-impermea(cid:173)
`ble multi-layered container containing the formulation,
`which container is comprised of an inner layer in direct
`contact with the formulation, which inner layer com(cid:173)
`prises a polyolefin; and an outer layer comprising a
`metal foil. Within this group of dispensing units, certain
`subgroups are preferred.
`One preferred subgroup are those dispensing units
`wherein the lower alkanol is selected from the group
`consisting of isopropyl alcohol and ethanol, and the
`thickening agent is selected from the group consisting
`of a carboxyvinyl polymer and hydroxypropyl ceIJu(cid:173)
`lose. Within this subgroup a preferred class of dispens(cid:173)
`ing units are those dispensing units wherein the formula(cid:173)
`tion is further comprised of an effective amount of a
`penetration enhancer; an effective amount of a chelating
`agent; and an effective amount of an antioxidant. Within
`this class a preferred subclass of dispensing units are
`those dispensing units wherein the penetration enhancer
`is selected from the group consisting of diisopropyl
`adipate, l-dodecylazacycloheptan-2-one, and oleic acid;
`the chelating agent is selected from the group consisting
`of the disodium salt of EDT A and citric acid; and the
`antioxidant is selected from the group consisting of
`BHT and BHA. Within this subclass the most preferred
`dispensing units are those dispensing units wherein the
`formulation is comprised of about 1.0% w /w of ketoro(cid:173)
`lac tromethamine; about 35.0% w/w of isopropyl alco(cid:173)
`hol; about 2.0% w/w of diisopropyl adipate; about
`0.0 1% w /w of the disodium salt of EDT A; about om %
`w/w of BHT; about 2.5% w/w of carbomer 940; and
`water q.s.
`Another preferred subgroup of dispensing units are
`those dispensing units wherein the inner layer is an
`ethylene/acrylic acid co-polymer and the outer layer is
`aluminum foil. Within this subgroup a preferred class of
`dispensing units are those units wherein the inner layer
`is between about 1.0 and 3.2 mils thick and the outer
`layer is between about 0.7 and 1.5 mils thick. Within this
`class the more preferred dispensing units are those dis(cid:173)
`pensing units wherein the container is in the shape of a
`deformable tube. Within this class the most preferred
`dispensing units are those dispensing units wherein the
`containers are deformable tubes sold under the trade(cid:173)
`name Glaminate ® (American Can Company).
`Presently, the most preferred dispensing units of the
`invention are those dispensing units wherein the ketoro(cid:173)
`lac topical gel formulation is comprised of about 1.0%
`w/w of ketorolac tromethamine, about 2.0% w/w of
`diisopropyl adipate, about 35.0% w/w of isopropyl
`alcohol, about 0.01% w/w of the disodium salt of
`EDTA, about 0.01 % w/w of butylated hydroxytolu-
`
`3 of 5
`
`

`

`5,091,182
`
`5
`ene, about 2.5% w /w of carbomer 940, and water q.s. to
`100%; and the gas-impermeable multi-layered container
`containing the formulation is comprised of an inner
`layer of a ethylene/acrylic acid co-polymer of about 1.0
`to 3.2 mils thick and an outer layer of aluminum foil of 5
`about 0.7 to 1.5 mils thick.
`The following example is given to enable those
`skilled in the art to more clearly understand and to
`practice the instant invention. It should not be consid(cid:173)
`ered as a limitation on the scope of the invention, but 10
`merely as being illustrative and representative thereof.
`
`EXAMPLE I
`A. This example illustrates the preparation of a repre(cid:173)
`sentative dispensing unit for a 1.0% ketorolac topical 15
`gel formulation.
`
`Ingredient
`
`%w/w
`
`6
`changes may be made and equivalents may be substi(cid:173)
`tuted without departing from the true spirit and scope
`of the invention. In addition, many modifications may
`be made to adapt a particular situation, material, com(cid:173)
`position of matter, process, process step or steps, to the
`objective, spirit and scope of the present invention. All
`such modifications are intended to be within the scope
`of the claims appended hereto.
`What is claimed is:
`1. A dispensing unit for a ketorolac topical gel formu(cid:173)
`lation, wherein said dispensing unit comprises:
`(a) a ketorolac topical gel formulation comprising:
`(i) ketorolac, or a pharmaceutically acceptable salt
`thereof, in an amount between 0.1 % and 5.0%
`w/w;
`(ii) a lower alkanol in an amount between 30% and
`45% w/w;
`(iii) a thickening agent in an amount sufficient to
`gel said formulation; and
`(iv) water q.s. to 100%; and
`(b) a gas-impermeable multi-layered container con(cid:173)
`taining said formulation, which container consists
`of consecutive layers which are firmly adhered to
`each other to make a unitary structure, wherein:
`(i) the inner layer comprises a polyolefin and is in
`direct contact with said formulation; and
`(ii) an outer layer comprises a metal foil.
`2. A dispensing unit of claim 1 wherein said lower
`alkanol is selected from the group consisting of isopro(cid:173)
`pyl alcohol and ethanol; and said thickening agent is
`selected from the group consisting of a carboxyvinyl
`polymer and hydroxypropyl cellulose.
`3. A dispensing unit of claim 2 wherein said formula-
`tion further comprises:
`(a) an effective amount of a penetration enhancer;
`(b) an effective amount of a chelating agent; and
`(c) an effective amount of an antioxidant.
`4. A dispensing unit of claim 3 wherein said penetra(cid:173)
`tion enhancer is selected from the group consisting of
`diisopropyl adipate,
`l-dodecylazacycloheptan-2-one,
`and oleic acid; said chelating agent is selected from the
`group consisting of the disodium salt of EDT A and
`citric acid; and said antioxidant is selected from the
`group consisting of BHT and BHA.
`S. A dispensing unit of claim 4 wherein said formula-
`tion comprises:
`(a) l.0% w/w of ketorolac tromethamine;
`(b) 35.0% w/w of isopropyl alcohol;
`(c) 2.0% w/w of diisopropyl adipate;
`(d) 0.01% w/w of EDT A disodium salt;
`(e) 0.Q1% w/w ofBHT;
`(f) 2.5% w/w of a synthetic polymer of approxi(cid:173)
`mately 1,250,000 to 4,000,000 molecular weight
`Composed of acrylic acid crosslinked with allyl
`ethers of sucrose or pentaerythritol; and
`(g) 0.18% w/w of tromethamine; and
`(h) water q.s.
`6. A dispensing unit of claim 4 wherein said formula-
`tion comprises:
`(a) 2.0% w/w of ketorolac tromethamine;
`(b) 35.0% w/w of isopropyl alcohol;
`(c) 2.0% w/w of diisopropyl adipate;
`(d) 0.01 % w/w of EDT A disodium salt;
`(e) 0.01% w/w of BHT;
`(f) 2.5% w/w of a synthetic polymer of approxi(cid:173)
`mately 1,250,000 to 4,000,000 molecular weight
`
`20
`
`25
`
`1.0
`ketorolac tromethamine
`2.0
`diisopropyl adipate
`35.0
`isopropyl alcohol
`0.01
`EDTA disodium salt
`0.01
`BHT
`2.5
`carbomer 940
`0.18
`tromethamine
`100.00
`purified water q.s. to
`----~------~-----------------------
`The above 1.0% ketorolac topical gel formulation
`was prepared by dissolving the ketorolac trometha(cid:173)
`mine, EDT A disodium salt and tromethamine in puri(cid:173)
`fied water to form an aqueous solution. (Tromethamine 30
`was added to maintain the pH of the formulation at pH
`4.2±0.2.) The diisopropyl adipate and butylated hy(cid:173)
`droxytoluene were then dissolved in the isopropyl alco(cid:173)
`hol to form an alcoholic solution. Carbomer 940 was
`then slowly dispersed in this alcoholic solution so as to 35
`avoid gelling. After the carbomer 940 was completely
`dispersed, the aqueous solution containing ketorolac
`tromethamine was then added to the alcoholic solution.
`The resulting mixture was then brought up to weight
`with purified water and, if needed, the pH was adjusted 40
`with either tromethamine or hydrochloric acid to main(cid:173)
`tain the pH of the formulation at 4.2±0.2. The resulting
`formulation was then slowly stirred at temperatures
`below 20' C. until gelling of the formulation was com-
`plete.
`Dispensing units containing the above formulation
`were prepared by filling Glaminate ® tubes, supplied
`by American Can Company, with the formulation by
`conventional methods known to those skilled in the art.
`B. In a similar manner, dispensing uruts for the fol- SO
`lowing 2.0% ketorolac topical gel formulation were
`prepared:
`
`45
`
`______ I~np~ed_ie_n_t __________________ % __ w_/w _________ 55
`2.0
`2.0
`35.0
`om
`0.01
`2.S
`100.00
`
`ketorollC tromethamine
`diisopropyl adipate
`iaopropyl alcohol
`EDT A disodium aalt
`BHT
`carbomer 940
`purified water q.s. to
`
`60
`
`C. In a similar manner, dispensing units for ketorolac
`topical gel formulations containing 0.1% to 5.0% w/w
`ketorolac tromethamine were prepared.
`While the present invention has been described with
`reference to the specific embodiments thereof, it should
`be understood by those skilled in the art that various
`
`65
`
`4 of 5
`
`

`

`5,091,182
`
`7
`composed of acrylic acid crosslinked with allyl
`ethers of sucrose or pentaerythritol; and
`(g) water q.s.
`7. A dispensing unit of claim 1 wherein said inner 5
`layer is an ethylenelacrylic acid co-polymer and said
`outer layer is aluminum foil.
`8. A dispensing unit of claim 7 wherein said inner
`layer is between about 1.0 and 3.2 mils thick and said 10
`outer layer is between about 0.7 and 1.5 mils thick.
`
`8
`9. A dispensing unit of claim 8 wherein said container
`is in the shape of a deformable tube.
`10. A dispensing unit of claim 5 wherein said inner
`layer of said container is an ethylene/acrylic acid co(cid:173)
`polymer and said outer layer is aluminum foil.
`11. A dispensing unit of claim 10 wherein said inner
`layer is between about 1.0 and 3.2 mils thick and said
`outer layer is between about 0.7 and 1.5 mils thick.
`12. A dispensing unit of claim 11 wherein said con(cid:173)
`tainer is in the shape of a deformable tube.
`• • • • •
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5 of 5
`
`