United States Patent 19
`Faring et al.
`
`(54) AQUEOUS GEL RETINOID DOSAGE FORM
`(75. Inventors: Richard K. Farng, East Brunswick;
`Gerard J. Gendimenico, Neshanic
`Station.James A. Meiss, East
`Brunswick, Shirley M. Ng,
`Bridgewater Stanley B. Wrobel, Jr.,
`Middlesex, all of N.J.
`(73) Assignee: Ortho Pharmaceutical Corporation,
`Raritan, N.J.
`
`21 Appl. No.: 444,145
`22 Filled:
`May 18, 1995
`4)
`)
`Related U.S. Application Data
`(63) Continuation of Ser. No. 132,014, Oct 5, 1993, abandoned,
`Which is a continuation of Ser. No. 869,684, Apr. 16, 1992,
`abandoned.
`int. Cl. ............. A61K 7/00; A61K 7/48
`(51
`52 U.S. Cl. .......................... 424/401; 514/994; 514/947;
`514/975; 514/859
`58 Field of Search ............................. 424/401; 514/844,
`514/947, 847,944, 975, 859; 568/824
`
`IIIHIII
`US005643584A
`11
`Patent Number:
`5,643,584
`45 Date of Patent:
`Jul. 1, 1997
`
`56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`424/318
`3,729,568 4/1973 Kligman
`... 514,438
`4,826,871
`5/1989 Gressel.
`... 424/489
`4,966,773 10/1990 Gressel ...........
`5,476,852 12/1995 Cauwenbergh ......................... 54/252
`
`
`
`DOC
`FOREIGN P.
`90/14082 11/1990 WIPO.
`90/14833 12/1990 WIPO
`
`S
`
`Primary Examiner-Sallie M. Gardner
`57
`ABSTRACT
`This invention relates to aqueous gel retinoid compositions
`and their methods of use. More specifically, the aqueous gel
`retinoid compositions of the invention utilize micronized
`particles of retinoids, particularly tretinoin, to provide an
`aqueous gel for topical application of such retinoids to the
`skin which minimizes skin irritation while retaining drug
`efficacy.
`
`33 Claims, No Drawings
`
`Apotex, Inc. (IPR2019-00400), Ex. 1020, p. 001
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`5,643,584
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`1.
`AQUEOUS GEL RETINOID DOSAGE FORM
`This is a continuation, of application Ser. No. 08/132,
`014, filed Oct. 5, 1993, now abandoned, which is a 1.60
`continuation of Ser. No. 07/869,684, now abandoned, filed
`Apr. 16, 1992, which are hereby incorporated by reference.
`FIELD OF THE INVENTION
`This invention relates to aqueous gel vehicles for retin
`oids. More specifically, micronized particles of retinoids,
`particularly tretinoin, are incorporated into aqueous gel
`vehicles to provide a gel composition for topical application
`of such retinoids to the skin.
`BACKGROUND OF THE INVENTION
`Retinoids (e.g. Vitamin A and its derivatives) are sub
`stances which are known to have a broad spectrum of
`biological activity. More specifically, these substances affect
`cell growth, differentiation and proliferation. Retinoids
`affect the differentiation, maintenance, and proliferation of
`many types of cells, whether they are of ectodermal, endo
`dermal or mesodermal origin. Retinoids have found clinical
`utility in the treatment of acne vulgaris, severe cystic acne,
`psoriasis, and other disorders of keratinization. Possible uses
`of retinoids are being explored in the prophylaxis and
`treatment of cancer. See generally, Pawson, B. A. et al.,
`"Retinoids at the Threshold: Their Biological Significance
`and Therapeutic Potential", Journal of Medicinal Chemistry
`25:1269-1277 (1982).
`It is known to use certain retinoids, particularly tretinoin,
`topically for treatment of acne as set forth in U.S. Pat. No.
`3,729,568. Other known topical uses of tretinoin include, in
`addition to ache treatment, treatment of senile comedones,
`nevus comedonicus, linear verrucous nevus, plantar warts,
`pseudofolliculitis, keratoacanthoma, solar keratosis of
`extremities, callosities, keratosis palmaris et plantaris, Dari
`35
`er's disease, ichthyosis, psoriasis, acanthosis nigricans,
`lichen planus, molluscum contagiosum, reactive perforating
`collagenosis, melasma, corneal epithelial abrasion, geo
`graphic tongue, Fox-Fordyce disease, cutaneous metastatic
`melanoma and keloids or hypertrophic scars see, e.g.,
`Thomas, J. R., et al., “The Therapeutic uses of Topical
`Vitamin AAcid', Journal of American Academy of Derma
`tology 4:505-516 (1981).
`U.S. Pat. No. 4,603,146 discloses methods for treating
`Sundamaged human skin topically with tretinoinin an emol
`45
`lient vehicle. U.S. Pat. Nos. 4,877,805 and 4,883,342 dis
`close methods for the treatment of Sundamaged human skin
`using retinoids. U.S. Pat. No. 5,051,449 discloses treatment
`of cellulite with retinoids.
`The above-noted patents disclose formulations of retin
`oids in various moisturizing bases such as creams or oint
`ments. Retinoids, such as tretinoin, in cream formulations,
`may meet the needs of certain individuals but may be found
`undesirable by other individuals. It is also suggested in
`European Patent Application No. 90303826.3 to Maxam,
`Inc. that volatile vehicles, such as alcohols, which may dry
`or otherwise harm the skin should be avoided. Maxam's
`patent application discloses an aqueous gel formulation of
`tretinoin which utilizes a glycerin and a proteinaceous
`material, e.g. soluble animal collagen, to stabilize its gelling
`agent. The present invention does not require the use of
`glycerin nor a proteinaceous material to stabilize its gel
`formulation.
`SUMMARY OF THE INVENTON
`It is therefore an object of the present invention to provide
`a retinoid aqueous gel composition for topical administra
`
`50
`
`40
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`65
`
`2
`tion of retinoid to the skin which minimizes skin irritation
`but maintains a high degree of therapeutic effectiveness.
`As embodied and fully described herein, the present
`invention provides a retinoid aqueous gel composition for
`therapeutic topical administration of retinoid to the skin
`comprising a therapeutically effective amount of micronized
`retinoid particles; a surfactant in an amount effective to
`enhance penetration of retinoid into the skin; a preservative;
`a gelling agent composition in an amount sufficient to
`provide body to the aqueous gel; and water qs to 100%. In
`preferred embodiments the composition comprises in weight
`by total weight of the composition: 0.0001 to 0.5% micron
`ized retinoid particles; 0.001 to 1.0% surfactant; 0.005 to
`2.0% preservative; 0.01% to 0.3%. antioxidant; 1.0% to
`2.0% gelling agent; sufficient base to attain a pH in the range
`of 4.0 to 7.0; and water qs to 100%.
`In preferred embodiments of the invention, the retinoid is
`tretinoin. In other preferred embodiments, the micronized
`particles comprise at least 90% of the particles in a size
`range of from 1 to 40 microns, more preferably from 1 to 30
`microns, and most preferably with a mean size in the range
`of 1 to 10 microns. In preferred embodiments the surfactant
`of the aqueous gel composition is selected from the group
`consisting of octoxynol, polyethylene glycol glyceryl stear
`ate and monoxynol. In preferred embodiments the preserva
`tive is selected from the group consisting of benzyl alcohol,
`sorbic acid, pardbens, imidazolidinyl urea (imidurea) and
`combinations thereof, more preferably, a combination of
`benzyl alcohol and sorbic acid. In preferred embodiments of
`the composition, the gelling agent is selected from the group
`consisting of acrylic acid crosslinked with the allyl ether of
`sucrose or pentaerythritol; and poloxamer. Preferably, the
`gelling agent is an acrylic acid polymer known to the art as
`carbomer. In preferred embodiments of the invention, the
`base used to raise the pH of the composition to a pH of
`between 4.0 to 7.0 is sodium hydroxide or triethanolamine,
`preferably, sodium hydroxide which is added in an amount
`of about 0.1% to 0.6% to provide a pH to the composition
`of between 4.5 to 5.5. In preferred embodiments of the
`invention the antioxidant is butylated hydroxytoluene
`(BHT), butylated hydroxyanisole (BHA), alpha-tocopherol,
`or ascorbic acid. In preferred embodiments of the invention
`the aqueous gel composition comprises from about 0.0001%
`to 0.5% retinoid, preferably, 0.01% to 0.2% retinoid.
`In a preferred embodiment of the invention the aqueous
`gel composition does not contain any water soluble lower
`alkyl alcohol.
`In other embodiments of the aqueous gel of the invention
`polyvinylpyrrollidone is added thereto to inhibit crystal
`growth of the micronized retinoids. In further preferred
`embodiments a chelating agent is added thereto.
`Methods of using the aqueous gel composition of the
`invention are provided to increase the therapeutic effective
`ness of retinoids for topical application to the skin compris
`ing the step of delivering a dispersion of micronized retinoid
`particles in an aqueous gel vehicle to the intended site of
`skin application. In preferred embodiments of the invention
`the method provides for delivering micronized retinoid to an
`intended site of application using an aqueous gel vehicle
`which has an alcohol content of less than 2% by weight of
`the total weight of the composition, more preferably the
`aqueous gel vehicle contains no water soluble lower alkyl
`alcohol.
`In other embodiments of the invention a method is
`provided for reducing the irritation associated with retinoid
`therapy which comprises the steps of incorporating micron
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`Apotex, Inc. (IPR2019-00400), Ex. 1020, p. 002
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`5,643,584
`
`3
`ized retinoid in an aqueous gel vehicle and applying the
`micronized retinoid aqueous gel composition to the skin of
`a patient. In preferred embodiments the aqueous gel com
`position used in this method comprises any of the preferred
`embodiments of the formulation described above.
`
`4
`inoin is present in the range of 0.005 to 0.2%. This concen
`tration range is particularly advantageous for topical appli
`cation of retinoid and particularly tretinoin particles to the
`skin of a patient because it provides optimal effective
`amounts of retinoid to the skin for treatment of acne and/or
`treatment of sundamaged skin and other therapeutic appli
`cations. Using tretinoin as a standard for retinoids, tretinoin
`will typically be present in the composition of the invention
`in an amount of about 0.001 to 0.5, preferably 0.005 to 0.2%
`weight by total weight, and other more or less potent
`retinoids will be used in corresponding amounts equivalent
`thereto.
`Larger amounts of retinoid, e.g. tretinoin, present in the
`formulations may increase the chance for skin irritation.
`Amounts which are less than those provided in this range
`may not provide enough retinoid or tretinoin to provide
`effective treatment to the skin of a patient.
`The retinoid aqueous gel composition of the invention
`comprises from about 0.001% to 1.0% surfactant, weight by
`total weight of the composition. The surfactant is useful to
`enhance the penetration of the retinoid into the epidermis
`layer of the skin and also to disperse the retinoid particles
`throughout the aqueous media. This dispersion is important
`to provide consistent dosage forms and applications of the
`drugs for application of optimal treatments to the skin of
`patients. Surfactants which are useful in accordance with the
`invention include but are not limited to those selected from
`the group consisting of octoxynol (an anhydrous mixture of
`mono p-(1,1,3,3-tetra-methylbutyl)phenyl]ethers of poly
`ethylene glycols containing 5 to 15 oxyethylene groups in
`the polyoxyethylene chain), polyethylene glycol glyceryl
`stearate and nonoxynol. Particularly preferred as a surfactant
`is octoxynol-13 (whereby an average of 13 oxyethylene
`groups are in the polyoxyethylene chain).
`The aqueous gel composition of the invention preferably
`comprises from about 0.005% to 2.0% preservative weight
`by total weight of the composition. The preservative is used
`to prevent spoilage of the aqueous gel during repeated
`patient use when it is exposed to contaminants in the
`environment from, for example, exposure to air or the
`patient's skin including contact with the fingers used for
`applying the therapeutic gel. Examples of preservatives
`useful in accordance with the invention include but are not
`limited to those selected from the group consisting of benzyl
`alcohol, sorbic acid, parabens, imidurea and combinations
`thereof. A particularly preferred preservative is a combina
`tion of about 0.5%-2.0% benzyl alcohol and 0.05% to 0.5%
`sorbic acid.
`The aqueous gel composition preferably includes an anti
`oxidant and a chelating agent which inhibit the degradation
`of the retinoid in the aqueous gel formulation. Preferred
`antioxidants are BHT, BHA, alpha-tocopherol and ascorbic
`acidin the preferred range of about 0.01% to 0.3% and more
`preferably BHT in the range of 0.03% to 0.1% by weight by
`total weight of the composition. Preferably, the chelating
`agent is present in an amount of from 0.01% to 0.5% by
`weight by total weight of the composition. Particularly
`preferred chelating agents include edetate salts (e.g. diso
`dium edetate) and citric acid in the range of about 0.01% to
`0.20% and more preferably in the range of 0.02% to 0.10%
`by weight by total weight of the composition. The chelating
`agent is useful for chelating metal ions in the composition
`which may be detrimental to the shelflife of the formulation.
`While BHT and disodium edetate are the particularly pre
`ferred antioxidant and chelating agent respectively, other
`Suitable and equivalent antioxidants and chelating agents
`may be substituted therefor as would be known to those
`skilled in the art.
`
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`O
`
`DETALED DESCRIPTION OF PREFERRED
`EMBODIMENTS OF THE INVENTION
`Reference will now be made in detail to preferred
`embodiments of the invention. Examples of the preferred
`embodiments are illustrated in the following Examples
`section.
`Retinoids have been defined narrowly as comprising
`vitamin A (retinol) and its derivatives, such as vitamin A
`15
`aldehyde (retinal) and vitamin Aacid (tretinoin), which are
`metabolites of vitamin A. Subsequent research has, however,
`resulted in a larger class of chemical compounds that are
`termed retinoids because they have biological actions simi
`lar to vitamin A, even though there may be structural
`dissimilarities. Compounds useful in the present invention
`include all natural and/or synthetic analogs of vitamin A or
`retinol-like compounds which have similar therapeutic
`activities as demonstrated for example, by tretinoin.
`Accordingly, as used herein for purposes of the present
`invention, the term "retinoid” will be understood to mean a
`natural or synthetic substance that elicits all or some of the
`biologic responses of retinoic acid or retinol by binding to
`and subsequently activating known and unknown cutaneous
`retinoic acid receptors. Also encompassed within the term
`"retinoid" for the purposes of the present invention, are
`stereoisomers of the retinoids, as well as pro-drugs thereof.
`Examples of retinoids include those disclosed in U.S. Pat.
`No. 4,877.805, the entire disclosure of this patent is hereby
`incorporated herein by reference.
`The present invention provides an aqueous gel composi
`tion for topical administration of retinoids to the skin which
`increases the therapeutic effectiveness of such an application
`over alcoholic gel vehicles or oil-based vehicles while
`reducing the irritation that is associated with the applications
`of retinoids to the skin of certain sensitive patients.
`The aqueous gel composition of the invention also pro
`vides for increasing the safety of topically applied retinoid
`to the skin whereby micronized retinoids are provided to an
`intended site of application using an aqueous gel vehicle
`which preferably contains no lower alkyl alcohols. This
`elimination of lower alkyl alcohol reduces potential prob
`lems of drying the skin as well as reducing volatile fumes
`which may be undesirably inhaled or be flammable during
`production of alcohol gel products.
`The aqueous gel composition of the invention comprises
`at least one retinoid in accordance with the definition
`described above. In preferred embodiments of the invention
`the retinoid is tretinoin. The retinoid, preferably tretinoin, is
`provided in a micronized form whereby at least 90% of the
`retinoid particles are provided in the size range of 1 to 40
`microns, more preferably 1 to 30 microns. Most preferably,
`the micronized retinoid particles have a mean size in the
`range of 1 to 10 microns. The retinoid particles which
`normally average above 40 microns to about 100 microns in
`size are reduced in particle size, i.e. micronized in accor
`dance with procedures known to the art such as using
`fluid-energy mills.
`The aqueous gel composition of the invention comprise in
`weight by total weight of the composition of from about
`0.0001 to 0.5% micronized retinoid, preferably tretinoin,
`particles. In more preferred embodiments micronized tret
`
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`5,643,584.
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`5
`The aqueous gel composition of the invention comprises
`a gelling agent which provides body to the aqueous gel
`vehicle and maintains the dispersion of retinoids in the
`vehicle by maintenance of the semisolid dosage form. Par
`ticularly preferred gelling agents are selected from the group
`consisting of acrylic acid polymers cross-linked with poly
`alkylsucrose; and poloxamer. More particularly, the gelling
`agent is an acrylic acid polymer crosslinked with the allyl
`ether of sucrose or pentaerythritol which are generally
`known as carbomers. Carbomers are sold under the trade
`mark CARBOPOL, in various grades. The more useful
`grades for the purposes of the present invention are 934,
`934P, 940, 941, 980 and 981 with 940 being the most
`preferred. These numbers designate the molecular weight
`and the crosslinking of the carboxypolymethylene mol
`ecules. Carbomers are referenced and listed in USP XXII,
`1910-1912 (1990). While the gelling agents specifically
`identified above are presently preferred, other suitable and
`equivalent gelling agents may be substituted therefor as
`would be known to those skilled in the art,
`In other optional embodiments of the invention polyvi
`nylpyrrollidone is added to the aqueous gel composition of
`the invention to inhibit crystal growth of the micronized
`retinoid and particularly, tretinoin. Optionally, about 0.1% to
`1.0%, and more preferably, 0.3% of polyvinylpyrrolidone by
`weight by total weight of the composition is added to the
`aqueous gel. Further, other additives such as about 5% to
`20% hydroxypropyl-beta-cyclodextrin (HPBCD) may be
`added to the formulation to enhance the availability of
`retinoid to the skin with reduced irritation.
`To achieve proper gelling of the formulation, the acidic
`carbomer gelling agent component is neutralized by the
`addition of a base thereto to form a gelling composition
`which provides body to the gel dosage form. In preferred
`embodiments enough base is added to the carbomer con
`taining aqueous gel compositions of the invention to provide
`35
`a pH of between 4.0 and 7.0, more preferably 4.5 to 5.5.
`While any suitable base may be used the preferred bases
`used to raise the pH of the aqueous gels of the invention are
`sodium hydroxide and triethanolamine. The exact amount of
`sodium hydroxide or triethanolamine that is added to an
`aqueous gel to achieve the desired pH range depends upon
`the amount of carbomer that is present in the aqueous gel
`composition. Generally, about 0.1% to 0.6% of pure sodium
`hydroxide by weight by total weight of the composition is
`added to provide a pH of the aqueous gel composition of the
`invention of between 4.0 and 7.0, more preferably 4.5 to 5.5.
`45
`Sodium hydroxide may be added to the aqueous gel com
`positions by means of a 10% aqueous solution for ease of
`handling and mixing.
`It is preferable in the aqueous gel composition of the
`invention to eliminate the presence of any water soluble
`alcohol such as isopropyl alcohol or ethanol from the
`formulation to prevent the potential deleterious affects of
`such alcohols, e.g. undesirable drying of the skin. While
`benzyl alcohol is a preferred antimicrobial preservative
`which is provided in amounts of about 0.5% to 2.0% by
`weight by total weight of the invention, it is not intended as
`a solubilizing alcohol as distinguished from water soluble
`alkyl alcohols which are intended as solubilizers for retin
`oids e.g. isopropanol or ethanol. The aqueous gel vehicle of
`the invention advantageously provides micronized retinoid
`as a dispersion and not a solution for topical application.
`The use of micronized retinoids and/or tretinoin particles
`represent a significant aspect of the present invention. The
`use of micronized particles of a water insoluble retinoid
`permits the use of an aqueous gel vehicle containing no
`solubilizing alcohol (e.g. no water soluble lower alkyl
`alcohol), to provide otherwise unattainable amounts of topi
`cal availability and penetration of retinoid into the skin. The
`
`6
`dispersion of the "extremely fine" micronized particles
`achieve good penetration of the retinoid into the skin with
`out significant passing of retinoid through the skin.
`Additional medicaments or active components may be
`used in combination with the retinoid dosage form compo
`sition of the invention. For example, antibiotics used in acne
`preparations such as: the antibacterials erythromycin,
`clindamycin, tetracycline, minocycline, of loxacin and
`sodium sulfacetamide; antifungals such as miconazole,
`terconazole, ketoconazole, econazole, fluconazole and clo
`trimazole; corticosteriods such as triancinolone, betametha
`sone and clobetasol; as well as other actives such as sulfur,
`anthralin, azelaic acid, alpha-hydroxy acids, benzoyl perox
`ide and skin growth factors; salts and derivatives of all of the
`above; and mixtures of any of the above may be added to the
`retinoid dosage form of the invention.
`As will be discussed below in the Examples section and
`the evaluation thereof, the aqueous gel formulations of the
`invention utilizing micronized tretinoin particles dispersed
`informulation components provide for increased therapeutic
`effectiveness of tretinoin for topical application to human
`skin. This result is unexpected and surprising in view of the
`state of the prior art which is focused on solubilizing
`retinoids in topical formulations. The present invention
`surprisingly achieves excellent topical skin penetration of
`retinoids in an aqueous dispersion while reducing deleteri
`ous side effects, e.g. irritation, thus improving the therapeu
`tic index of the composition of the invention over those
`retinoid preparations of the prior art.
`The invention will now be illustrated by examples. The
`examples are not intended to be limiting of the scope of the
`present invention but read in conjunction with the detailed
`and general description above, provide further understand
`ing of the invention and outline a process for preparing the
`compositions of the inventions and methods of practicing
`the invention.
`
`EXAMPLES
`The following ingredients, processes and procedures for
`preparing the compositions of the present invention corre
`spond to that described above. The procedures below
`describe with particularity the various formulation ingredi
`ents and procedures utilized. Any methods, starting
`materials, reagents or excipients which are not particularly
`described will be generally known and available to those
`skilled in the pharmaceutical formulation arts. All formula
`tion percentages are provided in percentage by weight by
`total weight of the composition.
`Example 1
`Micronized tretinoin (0.0001-0.1%)aqueous gels with a
`preferred preservative system:
`
`micronized tretinoin
`octoxynol-13 (IGEPAL*CA-720)
`sorbic acid
`benzyl alcohol
`disodium edietate
`ascorbic acid
`sodium metabisulfite
`carbomer (CARBOPOL 940)
`sodium hydroxide
`purified water qs
`
`0.0001-0.1%
`0.2%
`0.1%
`1.0%
`0.05%
`0.1%
`0.2%
`1.5%
`0.2%
`100%
`
`The aqueous gel of Example 1 was evaluated in an in vivo
`comparative study against a conventional alcohol gel. A
`formulation of a commercially available alcoholic gel in
`either of two strengths, 0.025% or 0.01% tretinoin, (vitamin
`A acid) by weight, comprises butylated hydroxytoluene,
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`7
`hydroxypropyl cellulose and alcohol in a gel vehicle. This
`formulation is utilized throughout the Examples section and
`designated as "Alcohol Gel (Comparative)". An evaluation
`and comparative of the aqueous gel of the invention and this
`conventional alcohol gel is provided below. The tests were
`carried out in accordance with the protocol and systems
`provided and explained in U.S. Pat. No. 4487,782 and
`Mezicket al., “Topical and Systemic Effects of Retinoids on
`Horn-Filled Utriculus Size in the Rhino Mouse. AModel to
`Quantify 'Antikeratinizing Effects of Retinoids”,Journal of
`Investigative Dermatology, 83:110-113(1984), the entire
`disclosure of which is hereby incorporated herein by refer
`CCC.
`In the following formulation evaluation EDso refers to
`measurements of efficacy (50% utriculus reduction); IDso
`refers to irritation (50% of maximum erythema grade of
`3.0); Rel. Potency is relative potency and F.L. is the fiducial
`limit.
`
`Rhino Mouse Utriculus Reduction
`Alcohol Gel (Comparative)
`
`%. Utriculus
`Reduction
`
`EDs
`
`Rel. Potency
`(95% F.L.)
`
`O.O08
`
`6.5
`21.1
`55.2
`69.5
`Aqueous Gel (Example 1)
`
`5,643,584
`
`8
`dure is used for investigating the in vitro skin permeation of
`tretinoin from the aqueous and alcoholic gel formulations:
`
`Human skin samples were kept frozen at -70° C. until
`use. Samples were thawed at room temperature for 30
`minutes, and then rinsed with normal saline. Skin samples
`were cut into appropriate sized pieces, tared, a 1 mm thick
`film of formulation was applied, and the samples were
`weighed. The skin was then mounted on a diffusion cell
`(modified Franz diffusion cells, 9 mm opening, 10 ml
`volume), which had previously been filled with receptor
`medium (10% HPBCD in water). Upon completion of the
`study (24 hours), the receptor medium was sampled. The
`excess formulation was wiped from the skin surface using a
`Kim-Wipe soaked in acetone, the skin surface was washed
`twice with water and once with acetone, wiping the skin
`surface with a Kim-Wipe after each wash. Each skin sample
`was placed into a volumetric flask and tretinoin was
`extracted.
`
`10
`
`5
`
`20
`
`The skin samples were extracted with methanol:ethyl
`acetate (1:1) with 0.5% BHT. Samples were sonicated 45
`minutes and a portion of the extracts were then assayed by
`HPLC.
`
`25
`
`Dose a
`
`0.0001
`0.001
`0.01
`0.05
`
`0,000
`0.001
`0.01
`0.05
`
`Dose %
`
`OOO
`0.01
`0.05
`
`0.0
`0.05
`0.1
`
`18.1
`31.6
`539
`69.1
`
`0.006
`
`1.7 (1.2, 2.6)
`
`30
`
`Rabbit Dermal titation
`Alcohol Gel (Comparative)
`Erythema
`Rel. Potency
`Grade
`(95% F.L.)
`
`IDso
`
`35
`
`OS
`1.3
`2.8
`Aqueous Gel (Example 1)
`
`0.007
`
`1.
`
`0.6
`1.
`1.6
`
`0.
`
`0.09 (0.05, 0.16)
`
`The results of the in vitro skin permeation of tretinoin
`from the formulation of Example 2 as compared to alcoholic
`gel (comparative) and two other comparative formulations
`whereby the formulation of Example 2 was altered to
`exclude the surfactant and to substitute unmicronized par
`ticles of tretinoin for micronized particles are all summa
`rized below:
`
`Formulation
`Alcoholic Gel (comparative)
`Aqueous Gel (Ex. 2)
`
`Aqueous Gel (Ex. 2)
`without surfactant
`Aqueous Gel (Ex. 2)
`with large (unmicronized)
`tretinoin particles
`
`45
`
`Amount
`in Skin
`
`Amount Passing
`Through Skin
`
`18 +/- 2 mcg
`30 +/- 1 mcg
`
`9.3 +/- 2 mcg
`
`0.4 mcg
`0.0 mcg
`(below
`detection limit)
`0.0 mcg
`
`18 +/- 2 mcg
`
`0.0 mcg
`
`The aqueous gel of Example 1 is found to be more potent
`than the comparative alcohol gel on utriculus reduction, as
`demonstrated by the lower EDso for the aqueous gel and
`much less irritating to rabbit skin as indicated by the higher
`tolerated dose at IDso for the aqueous gel. The therapeutic
`index comprising the ratio of IDs/EDs (TL) for the
`aqueous gel of the invention is 0.1/0.006 (TI-17) vs. the
`comparative alcohol gel which is 0.007/0.008 (T.I.=1).
`Example 2
`
`tretinoin
`octoxynol-13 (IGEPALCA-720)
`sorbic acid
`benzyl alcohol
`disodium edietate
`alpha-tocopherol
`carbomer (CARBOPOL 940)
`sodium hydroxide
`purified water qs
`
`0.025%
`0.2%
`0.1%
`1.0%
`0.05%
`0.04%
`1.5%
`0.2%
`100%
`
`This formulation was tested for the extent of tretinoin
`penetration into human skin in vitro. The following proce
`
`50
`
`55
`
`The tretinoin aqueous gel of the presentinvention releases
`tretinoin into the upper layer of human skin but not any
`detectable amount passes through the skin. This example of
`an aqueous gel of the invention thus releases tretinoin into
`the skin as well as or better than the commercially available
`alcoholic gels without excess drug passing through the skin
`and without excess irritation.
`
`Further investigation of the aqueous gels of the invention
`versus comparison gels not containing a surfactant or con
`taining larger (unmicronized) particles of tretinoin indicates
`a drop in skin permeation of tretinoin of approximately
`3-fold and 2-fold respectively. Such results indicate that the
`use of a surfactant and micronized particles of tretinoin
`contribute to a surprising enhancement of tretinoin skin
`permeation from the aqueous gel formulations of the
`invention.
`
`65
`
`Apotex, Inc. (IPR2019-00400), Ex. 1020, p. 005
`
`

`

`9
`Example 3
`
`5,643,584
`
`10
`Formulation Evaluation
`
`Rhino Mouse Utriculus Reduction
`Alcohol Gel (Comparative)
`% Utriculus
`Reduction
`
`EDso
`
`Rel. Potency
`(95% F.L.)
`
`12.7
`26.6
`63.9
`76.2
`Aqueous Gel (Example 4)
`
`0.004
`
`1.
`
`12.5
`23.2
`64.8
`750
`
`0.005
`
`09 (0.6, 1.4)
`
`Rabbit Dermal Irritation
`Alcohol Gel (Comparative)
`Erythema
`Grade
`
`IDso
`
`Rel. Potency
`(95% F.L.)
`
`0.1
`0.9
`2.6
`Aqueous Gel (Example 4)
`
`0.01
`
`1
`
`O
`0.3
`1.6
`
`0.12
`
`0.2 (0.08, 0.5)
`
`Dose %
`
`0.0001
`0.001
`0.01
`0.05
`
`0.0001
`0.001
`0.01
`0.05
`
`Dose %
`
`0.001
`0.01
`0.05
`
`0.001
`0.01
`0.1
`
`Micronized tretinoin (0.0001-0.1%) aqueous gels with
`polyvinylpyrrolidone:
`
`micronized tretinoin
`octoxynol-13 (IGEPAL*CA-720)
`methyl paraben
`propyl paraben
`benzyl alcohol
`disodium edietate
`ascorbic acid
`polyvinylpyrrollidone
`carbomer (CARBOPOL*934)
`sodium hydroxide
`purified water qs
`
`0.0001-0.1%
`0.2%
`0.18%
`0.02%
`1.0%
`0.05%
`0.1%
`0.3%
`1.5%
`0.16%
`100%
`
`Formulation Evaluation
`
`10
`
`15
`
`20
`
`Rhino Mouse Utriculus Reduction
`Alcohol Gel (Comparative)
`%. Utriculus
`Reduction
`
`EDso
`
`Rel. Potency
`(95% FL.)
`
`25
`
`Dose %
`
`0.0001
`0.001
`0.01
`0.05
`
`0.0001
`0.001
`0.01
`0.05
`
`Dose %
`
`0.001
`0.01
`0.05
`
`0.001
`0.01
`0.05
`
`12.0
`28.5
`64.4
`77.1
`Aqueous Gel (Example 3)
`
`0.004
`
`1.
`
`7.9
`31.6
`59.6
`76.5
`
`0.004
`
`09 (0.7, 1.1)
`
`Rabbit Dermal Erritation
`Alcohol Gel (Comparative)
`Erythema
`Grade
`
`Dso
`
`0.1
`0.9
`2.6
`Aqueous Gel (Example 3)
`
`0.01
`
`Rel. Potency
`(95% FL.)
`
`0
`0.3
`19
`
`0.06
`
`0.3 (0.1, 07)
`
`45
`
`30
`
`35
`
`The above aqueous gel is found to be as potent as the
`alcohol gel on utriculus reduction, but was much less
`irritating to rabbit skin (aqueous gel TL=24 vs. alcohol gel
`TL=2.5).
`
`Example 5
`
`micronized tretinoin
`octoxynol-13 (IGEPAL* CAT20)
`sorbic acid, N.F
`benzyl alcohol, NF
`disodium edetate, NF
`citric acid, USP
`butylated hydroxytoluene, NF
`carbomer (CARBOPOL*940), NF
`sodium hydroxide, USP
`purified water, USP qs
`
`0.0001-0.5%
`0.2%
`0.1%
`1.0%
`0.05%
`0.1%
`0.05%
`1.5%
`0.2%
`100%
`
`The above tretinoin aqueous gel composition is expected
`to provide similar advantageous results analogous to those
`formulations of the invention evaluated above.
`The above evaluations and test results demonstrate the
`utility of the formulations of the invention for increasing the
`effective therapeutic index, i.e. Do/EDso for topical admin
`istration of retinoids, particularly, tretinoin on the skin of a
`patient. The increased therapeutic index is achieved by
`requiring higher amounts of active (retinoid) to produce a
`specific threshold of irritation (IDs) and lower amounts to
`produce a specific threshold of efficacy (EDs) in the aque
`ous gel formulations of the invention.
`The scope of the present invention is not limited by the
`description, examples and suggested uses herein and modi
`fications can be made without departing from the spirit of the
`invention. The formulations of the invention may, for
`example, have other applications and uses in addition to
`those described herein.
`Applications of the compositions and methods of the
`present invention for medical or pharmaceutical uses can be
`
`This aqueous gel is found to be as potent as the alcohol gel
`on utriculus reduction, but was much less irritating to rabbit
`skin (aqueous gel T.L=15 vs. alcohol gel T.I.=2.